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CORK Bibliography: Alcohol Metabolism

84 citations. January 2005 to present

Prepared: March 2009

Chen CC; Yin SJ. Alcohol abuse and related factors in Asia. International Review of Psychiatry 20(5): 425-433, 2008. (78 refs.)

Alcohol problems are a global issue, and the nature of alcohol abuse is very complicated. The susceptibility to alcohol abuse varies greatly from one individual to another and also from one nation to another, depending on the availability of alcohol, a country's regulation related to alcohol, a country's cultural background, religious tradition and its economics. Alcohol dependence is also a complicated disease process. The prevalence of alcohol dependence also varies greatly from one ethnic group to another. Asia is the world's largest and most populous continent. The natural disasters, religious conflicts as well as political disputes cause people lack of opportunity in many countries. People in this region do not consume more alcohol than the people in the rest of the world. The prevalence of alcohol dependence is not as high as is seen in other regions. In Asia, not only socio-economic factors, but also biological factors influence drinking behaviour. Findings of functional genetic polymorphism of the major alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) have led to the suggestion that this enzyme system may possibly play a diverse but critical role in alcohol dependence and in the alcohol-related disease process in the different ethnic groups. This paper reviews alcohol problems and related factors. Their management and prevention strategy are discussed.

Dakeishi M; Murata K; Sasaki M; Tamura A; Iwata T. Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers. Alcohol and Alcoholism 43(2): 143-147, 2008. (36 refs.)

Aims: The objective was to clarify the effect of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) genotypes on the diabetic risk in Japanese workers. Methods: At the time of mandatory health checkup, the ADH2 and ALDH2 genotypes, as well as fasting plasma glucose (FPG) levels, body mass index (BMI), smoking habit, and weekly alcohol intake, were examined in 492 men and 183 women working at motor vehicle dealerships. Results: In using two-way analysis of variance to manipulate ADH2 and ALDH2 genotypes and alcohol intake (70 g/week for men and 35 g/week for women), the FPG level after the adjustment for age, BMI, smoking habit, and another genotype was significantly higher in the men with ADH21/1 genotype than in those with the other genotypes, but there was no significant difference in the FPG level between the men with and without ALDH21/1 genotype. In contrast, the women with ALDH21/1 genotype had significantly lower FPG levels than those with the other genotypes, but there was no significant difference in the FPG level between the women with and without ADH21/1 genotype. Also, a significant interaction between ethanol intake and ALDH2 genotypes was seen only in the women. Conclusions: These findings suggest that genotypes of ADH2 and ALDH2 can modify the diabetic risk, irrespective of amounts of alcohol consumed. Also, there may be sex differences in the effect of these enzyme genotypes on glucose metabolism.

Gao CM; Takezaki T; Wu JZ; Zhang XM; Cao HX; Ding JH et al. Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males. World Journal of Gastroenterology 14(32): 5078-5083, 2008. (22 refs.)

AIM: To evaluate the relationship between drinking and polymorphisms of alcohol dehydrogenase 2 (ADH2) and/or aldehyde dehydrogenase 2 (ALDH2) for risk of colorectal cancer (CRC) in Chinese males. METHODS: A case-control study was conducted in 190 cases and 223 population-based controls. ADH2 Arg47His (G-A) and ALDH2 Glu487Lys (G-A) genotypes were identified by PCR and denaturing high-performance liquid chromatography (DHPLC). Information on smoking and drinking was collected and odds ratio (OR) was estimated. RESULTS: The ADH2 A/A and ALDH2 G/G genotypes showed moderately increased CRC risk. The age- and smoking-adjusted OR for ADH2 A/A relative to G/A and G/G was 1.60 (95% CI=1.08-2.36), and the adjusted OR for ALDH2 G/G relative to G/A and A/A was 1.79 (95% CI=1.19-2.69). Significant interactions between ADH2, ALDH2 and drinking were observed. As compared to the subjects with ADH2 G and ALDH2 A alleles, those with ADH2 A/A and ALDH2 G/G genotypes had a significantly increased OR (3.05, 95% CI= 1.67-5.57). The OR for CRC among drinkers with the ADH2 A/A genotype was increased to 3.44 (95% CI= 1.84-6.42) compared with non-drinkers with the ADH2 G allele. The OR for CRC among drinkers with the ALDH2 G/G genotype was also increased to 2.70 (95% CI= 1.57-4.66) compared with non-drinkers with the ALDH2 A allele. CONCLUSION: Polymorphisms of the ADH2 and ALDH2 genes are significantly associated with CRC risk. There are also significant gene-gene and gene-environment interactions between drinking and ADH2 and ALDH2 polymorphisms regarding CRC risk in Chinese males.

Harrigan GG; Maguire G; Boros L. Metabolomics in alcohol research and drug development. Alcohol Research & Health 31(1): 26-35, 2008. (37 refs.)

Developers of new medications need to describe and predict the functional attributes of test compounds administered to cells, animals, and humans. Today, researchers increasingly appreciate the role that intermediary products (i.e., metabolites) generated in the course of various metabolic pathways play in both health and disease states and how their analysis can support development of new medications. Advances in analytical and computational techniques have facilitated the rise of new and powerful tools for measuring metabolic and biochemical pathways in such complex systems. Metabolomics -- a systems biology approach to characterizing metabolites produced in biochemical pathways -- is contributing to many studies of disease progression and treatment, although it has not yet been extensively applied in research on metabolic perturbations associated with alcohol abuse. However, numerous metabolomic approaches may contribute to alcohol-related research, as illustrated by studies on alcohol-related metabolic dysfunctions such as (1) alterations in fat metabolism and (2) thiamine deficiency. By further increasing the number and types of metabolites that can be measured in a given biological sample, metabolomic approaches may be able to help define the role of the many different metabolic pathways affected by alcohol abuse and support discovery and development of novel medications for the treatment of alcoholism and related conditions.

Public Domain

Helander A; Bottcher M; Fehr C; Dahmen N; Beck O. Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification. Alcohol and Alcoholism 44(1): 55-61, 2009. (41 refs.)

Aims: Ethyl glucuronide (EtG) and ethyl sulfate (EtS) are conjugated ethanol metabolites formed in low amounts after alcohol consumption. Compared with ethanol, EtG and EtS are excreted in urine for a prolonged time, making them useful as sensitive alcohol biomarkers. This study determined the detection times for EtG and EtS in alcoholic patients undergoing alcohol detoxification. Methods: Alcohol-dependent patients (n = 32) with an initial alcohol concentration >= 1 g/L based on breath testing were followed during detoxification. Urine samples for determination of EtG, EtS, ethanol and creatinine were collected on admission to the hospital and thereafter once daily for several days. EtG and EtS measurements were performed by liquid chromatography-mass spectrometry (LC-MS) and EtG also using an immunochemical assay (DRI-EtG EIA, ThermoFisher/Microgenics). Results: The detection time for urinary EtG was weakly correlated (r = 0.434, P = 0.013) with the initial alcohol concentration (range 1.0-3.4 g/L). For EtG, the individual time range until return to below the applied cut-off limit (< 0.5 mg/L) was similar to 40-130 h (median 78) with a similar time course observed for EtS. After correction for urine dilution, the time until an EtG/creatinine ratio < 0.5 mg/g was similar to 40- 90 h (median 65). The detection times after an estimated zero ethanol concentration were similar to 30-110 h (median 66) for EtG and similar to 30- 70 h (median 56) for EtG/creatinine. The EtG results by LC-MS and the immunoassay were in good agreement. Conclusions: During alcohol detoxification, EtG and EtS remained detectable in urine for several days. The detection times showed wide inter-individual variations, also after adjusting values for urine dilution and to the estimated times for a completed ethanol elimination.

Hipolito L; Sanchez-Catalan MJ; Polache A; Granero L. Induction of brain CYP2E1 changes the effects of ethanol on dopamine release in nucleus accumbens shell. Drug and Alcohol Dependence 100(1-2): 83-90, 2009. (61 refs.)

CYP2E1 is an important enzyme involved in the brain metabolism of ethanol that can be induced by chronic consumption of alcohol. Recent works have highlighted the importance of this system in the context of the behavioural effects of ethanol. Unfortunately, the underlying neurochemical events for these behavioural changes, has not been yet explored. In this work, we have started this exploration by analyzing the possible changes in the neurochemical response of the mesolimbic system to ethanol after pharmacological induction of brain CYP2E1. We have used the clopamine extracellular levels in nucleus accumbens (NAc) core and shell, measured by means of microdialysis in vivo, as an index of the effects of ethanol. Acetone 1% in the tap water was used to induce brain CYP2E1. Efficacy of the induction protocol was assessed by immunoblotting. Intravenous administration of 1.5 g/kg of ethanol in control rats provoked a significant increase of the dopamine levels in both the core (up to 127% of baseline) and the shell (up to 122% of baseline) of the NAc. However, the same dose of ethanol in acetone-treated rats only increased the dopamine extracellular levels in the core (up to 142% of baseline) whereas dopamine levels in the shell subregion remain unaltered relative to baseline. The results of this study indicate that induction of CYP2E1 changes the response of the mesolimbic system to ethanol in a region-dependent manner. Two hypotheses are postulated to explain the observed effects.

Hosono S; Matsuo K; Kajiyama H; Hirose K; Suzuki T; Hiraki A et al. Reduced risk of endometrial cancer from alcohol drinking in Japanese. Cancer Science 99(6): 1195-1201, 2008. (38 refs.)

The role of alcohol consumption in the etiology of endometrial cancer has not been clarified. To examine the association between alcohol consumption and endometrial cancer risk, we conducted a case-control study with 148 histologically diagnosed incident endometrial cancer cases and 1468 matched non-cancer controls. Median consumption of alcohol was only 19.3 g/week among cases who drank and 28.2 g/week among controls who drank. These values are lower than in Western countries. Relative risk was analyzed in subjects classified into four groups according to weekly alcohol consumption (non-drinkers, 1-24 g/week, 25-175 g/week, and > 175 g/week). Confounder-adjusted odds ratios for those consuming alcohol at < 25 g/week, 25-175 g/week, and > 175 g/week compared to non-drinkers were 0.79 (95% confidence interval (CI), 0.49-1.28), 0.42 (95% CI, 0.23-0.79), and 0.47 (95% CI, 0.14-1.58), respectively. Further analysis was conducted concerning self-reported physical reaction to alcohol. Among women without flushing after drinking, a significant inverse association between risk and alcohol intake was seen (trend P = 0.001). In contrast, no protective effect of alcohol was seen among women who experience flushing after drinking. These results suggest the presence of an inverse association between alcohol drinking and endometrial cancer risk among Japanese women, and that this association is evident among those without flushing. Further investigation of these findings is warranted.

Husemoen LLN; Fenger M; Friedrich N; Tolstrup JS; Fredriksen SB; Linneberg A. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors. Alcoholism: Clinical and Experimental Research 32(11): 1984-1991, 2008. (59 refs.)

Background: Genetic variation in ethanol metabolism may have an influence on both alcohol drinking habits and the susceptibility to health effects of alcohol drinking. Such influences are likely to bias exposure-disease associations in epidemiologic studies of health effects of alcohol drinking. In a Caucasian population, we examined the association of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genetic variants with alcohol drinking habits, biomarkers of alcohol exposure, and risk factors for cardiovascular disease. Methods: The study population consisted of 1,216 Danish men and women aged 15-77 years participating in a health examination in 1998. The health examination included a self-administered questionnaire (alcohol drinking habits), a physical examination (blood pressure), and various blood tests [alanine aminotransferase (ALAT), erythrocyte mean corpuscular volume (E-MCV), and lipids]. ADH and ALDH gene variants were determined by standard techniques. Data were analyzed by regression analyses adjusted for relevant confounders. Results: Self-reported alcohol drinking was significantly associated with increasing levels of ALAT, E-MCV, high-density lipoprotein cholesterol, and blood pressure. The ALDH1b ala69val variant was associated with nondrinking and total alcohol intake. The ALDH2 promoter variant was associated with binge-drinking, and the ALDH1b1 ala69val polymorphism was associated with diastolic blood pressure. We did not find any statistically significant interactions between any of the gene variants and alcohol consumption in relation to the various outcomes. Conclusions: In this Caucasian population sample, we found evidence to support that genetic variation in ethanol metabolism may influence drinking habits, but no statistically significant gene-environment interactions. More large-scale epidemiologic studies are needed to confirm theses results and to further investigate genetic susceptibility to the effects of alcohol drinking.

Jelski W; Zalewski B; Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer. Journal of Clinical Laboratory Analysis 22(3): 204-209, 2008. (20 refs.)

The principal enzymes catalyzing the conversion of ethanol to acetate are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The activities of these enzymes are elevated in the serum during the course of alcoholism or cirrhosis. In previous investigations we have found elevated levels of ADH, ALDH, and class I ADH activity in liver cancer cells. It can suggest that these changes may be reflected by enzyme activity in the serum. In this work, the activity of ADH isoenzymes, and ALDH in the sera of patients with liver cancer was measured. Serum samples were taken from 64 patients (28 drinkers, 36 nondrinkers), with liver cancer. 25 patients had primary and 39 metastatic liver tumors. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorimetric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorimetric methods, with class-specific fluorogenic substrates. The activity of class III ADH was measured by the photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. A statistically significant increase of class I ADH isoenzymes was found in the sera of cancer patients. The median activity of this class isoenzyme in the total cancer group increased about 51% (2.94 mU/L) in the comparison to the control level (1.43 mU/L). The activity of the class I ADH isoenzyme was significantly higher in the sera of patients with metastatic tumors than with primary cancers. The activity of this class in the sera of drinkers and group of moderate drinkers was significantly higher in comparison to the control group and higher in the sera of heavy drinkers when compared with moderate drinking patients. The total ADH activity was significantly higher (44%) among patients with cancer than healthy ones. The activity of class I ADH isoenzymes was elevated only in the serum of patients with metastatic liver cancer. This increase of activity seems to be caused by the enzyme released from liver cancer cells and primary tumors originating in other organs.

Kim DJ; Choi IG; Park BL; Lee BC; Ham BJ; Yoon S et al. Major genetic components underlying alcoholism in Korean population. Human Molecular Genetics 17(6): 854-858, 2008. (20 refs.)

Alcohol metabolism is one of the biological determinants that could significantly be influenced by genetic polymorphisms in alcohol-metabolism genes. Alcohol dehydrogenase (ADH) converts alcohol to acetaldehyde, and aldehyde dehydrogenase (ALDH) converts acetaldehyde to acetate. The well-known genetic polymorphisms in ADH1B(His47Arg) and ALDH2(Glu487Lys) have dramatic effects on the rate of metabolizing alcohol and acetaldehyde, respectively. The protective allele of ADH1B (ADH1B*47His) encodes for a rapid ethanol-metabolizing enzyme, and the susceptible allele of the ALDH2 (ALDH2*487Lys) is strongly associated with decreased rate of metabolizing acetaldehyde. However, the combined genetic effects of both functional polymorphisms have not been clarified. The combined analysis of two polymorphisms among a Korean population (n = 1,032) revealed dramatic genetic effects on the risk of alcoholism. Individuals bearing susceptible alleles at both loci have 91 times greater risk for alcoholism [odds ratio (OR) = 91.43, P = 1.4 x 10(-32)] and individuals bearing one susceptible and one protective allele at either loci have 11 times greater risk (OR = 11.40, P = 3.5 x 10(-15)) compared with subjects who have both protective alleles. The attributable fraction of those genetic factors, calculated based on population controls, indicates that alcoholism in 86.5% of alcoholic patients can be attributed to the detrimental effect of ADH1B*47Arg and/or ALDH2*487Glu in Korean population.

Lowe ED; Gao GY; Johnson LN; Keung WM. Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. Journal of Medicinal Chemistry 51(15): 4482-4487, 2008. (50 refs.)

The ALDH2 *2 gene encoding the inactive variant form of mitochondrial aldehyde dehydrogenase (ALDH2) protects nearly all carriers of this gene from alcoholism. Inhibition of ALDH2 has hence become a possible strategy to treat alcoholism. The natural product 7-0-glucosyl-4'-hydroxyisoflavone (daidzin), isolated from the kudzu vine (Peruraria lobata), is a specific inhibitor of ALDH2 and suppresses ethanol consumption. Daidzin is the active principle in a herbal remedy for "alcohol addiction" and provides a lead for the design of improved ALDH2. The structure of daidzin/ALDH2 in complex at 2.4 A resolution shows the isoflavone moiety of daidzin binding close to the aldehyde substrate-binding site in a hydrophobic cleft and the glucosyl function binding to a hydrophobic patch immediately outside the isoflavone-binding pocket. These observations provide an explanation for both the specificity and affinity of daidzin (IC50 = 80 nM) and the affinity of analogues with different substituents at the glucosyl position.

Mello T; Ceni E; Surrenti C; Galli A. Alcohol induced hepatic fibrosis: Role of acetaldehyde. (review). Molecular Aspects of Medicine 29(1-2): 17-21, 2008. (37 refs.)

Alcohol abuse is one of the major causes of liver fibrosis worldwide. Although the pathogenesis of liver fibrosis is a very complex phenomenon involving different molecular and biological mechanisms, several lines of evidence established that the first ethanol metabolite, acetaldehyde, plays a key role in the onset and maintenance of the fibrogenetic process. This review briefly summarizes the molecular mechanisms underlying acetaldehyde pro-fibrogenic effects. Liver fibrosis represents a general wound-healing response to a variety of insults. Although mortality due to alcohol abuse has been constantly decreasing in the past 20 years in Southern Europe and North America, in several Eastern-European countries and Great Britain Alcoholic Liver Disease (ALD) shows a sharply increasing trend [Bosetti, C., Levi, F., Lucchini, F., Zatonski, W.A., Negri, E., La, V.C., 2007. Worldwide mortality from cirrhosis: an update to 2002. J. Hepatol. 46, 827-839]. ALD has a complex pathogenesis, in which acetaldehyde (AcCHO), the major ethanol metabolite, plays a central role. Ethanol is mainly metabolized in the liver by two oxidative pathways. In the first one ethanol is oxidized to acetaldehyde by the cytoplasmic alcohol dehydrogenase enzyme (ADH), acetaldehyde is then oxidized to acetic acid by the mitochondrial acetaldehyde dehydrogenase (ALDH). The second pathway is inducible and involves the microsomal ethanol-oxidizing system (MEOS), in which the oxidation of ethanol to acetaldehyde and acetic acid also leads to generation of reactive oxygen species (ROS). Chronic ethanol consumption significantly inhibits mitochondrial ALDH activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in a striking increase of tissue and plasma acetaldehyde levels [Lieber, C.S., 1997. Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 257, 59-84]. This review will focus oil the molecular mechanisms by which acetaldehyde promote liver fibrosis.

Mizoue T; Inoue M; Wakai K; Nagata C; Shimazu T; Tsuji I et al. Alcohol drinking and colorectal cancer in Japanese: A pooled analysis of results from five cohort studies. American Journal of Epidemiology 167(12): 1397-1406, 2008. (40 refs.)

Colorectal cancer is an alcohol-related malignancy; however, the association appears to be stronger among Asian populations with a relatively high prevalence of the slow-metabolizing aldehyde dehydrogenase variant. To examine the association between alcohol consumption and colorectal cancer in Japanese, the authors analyzed original data from five cohort studies that measured alcohol intake using validated questionnaires at baseline. Hazard ratios were calculated in the individual studies, with adjustment for a common set of variables, and then combined using a random-effects model. During 2,231,010 person-years of follow-up (ranging variously from 1988 to 2004), 2,802 colorectal cancer cases were identified. In men, multivariate-adjusted pooled hazard ratios for alcohol intakes of 23-45.9 g/day, 46-68.9 g/day, 69-91.9 g/day, and >= 92 g/day, compared with nondrinking, were 1.42 (95% confidence interval (CI): 1.21, 1.66), 1.95 (95% CI: 1.53, 2.49), 2.15 (95% CI: 1.74, 2.64), and 2.96 (95% CI: 2.27, 3.86), respectively (p for trend < 0.001). The association was evident for both the colon and the rectum. A significant positive association was also observed in women. One fourth of colorectal cancer cases in men were attributable to an alcohol intake of >= 23 g/day. An alcohol-colorectal cancer association seems to be more apparent in Japanese than in Western populations. Whether this difference can be ascribed to genetic or environmental factors needs to be clarified.

Rozin AP; Attias J; Presser D; Rosenberg H; Moscovitz M; Bentur Y. Alcohol poisoning and venous hyperoxia. Toxicology Mechanisms and Methods 18(9): 745-750, 2008. (25 refs.)

Venous PCO2 and PO2 in the presence of normal arterial PCO2 and PO2 in patients with alcoholic intoxication have not been previously evaluated. The objective of this study was to compare arterial and venous blood gases in patients with alcoholic intoxication and healthy controls. Sixteen patients with alcoholic intoxication and 20 controls underwent simultaneous blood sampling from a radial artery and an antecubital vein for acid-base analysis. Osmolality and ethanol blood concentration was estimated. Elevated venous pO(2) were found in 56% of patients with alcoholic poisoning compared with 15% of controls. A formula was found describing possible arterio-venous shunt accounting for elevated venous pO(2) and enabling calculation of the relevant venous carbon dioxide content and CO2 product. The values of the venous pO(2) and arterio-venous shunt were more significant in the alcohol group than in controls (p = 0.002, p = 0.001, respectively). Percentage of patients with a-v shunts was significantly higher in the alcohol group (81%) than in controls (25%) (p = 0.002, OR 2.6, 95% CI 0.13-6.52). The relevant venous CO2 and CO2 product had the non-significant trend to be higher in the alcohol group. In conclusion, this study reports ethanol-induced venous pO(2) and pCO(2) elevation. This may be associated with the effects of tissue perfusion stealing and high oxygen consumption. On the other hand, possible beneficial consequences may occur: acceleration of alcohol elimination and reduction of alcohol-induced tissue damage.

Taylor RE; Raysor BR; Kwagyan J; Ramchandani VA; Kalu N; Powell-Davis M et al. Alterations in ethyl alcohol pharmacokinetics during oral consumption of malt liquor beverages in African Americans. Alcoholism: Clinical and Experimental Research 32(12): 2074-2080, 2008. (36 refs.)

Malt liquor (ML) beverages have become increasingly popular among urban minority groups, due partly to their inexpensive price and targeted advertising. We hypothesized that nonfermented by-products contained in ML beverages will alter the pharmacokinetics (PK) and pharmacodynamic (PD) effects of its ethanol content. In addition, we determined the effect of alcohol dehydrogenase (ADH) genotypes on the PK following consumption of ML beverages. The study was conducted in 31 healthy adult African-American social drinkers, mean +/- SD age of 22.3 +/- 1.3 years, and weight of 70.7 +/- 10.9 kg. Participants were administered ethanol, in randomized order, 2-weeks apart, in the form of oral ML beverage (6%v/v), or isocaloric solution of diet soda-ethanol (DS-Etoh) beverage (6%v/v). During each session the beverage was consumed over 4 minutes and breath alcohol concentrations (BrAC) as well as subjective and behavioral effects of ethanol were evaluated over 180 minutes. Pharmacokinetic parameters of ethanol were calculated using Michaelis-Menten elimination kinetics. The effect of ML and ADH genotype on PK was evaluated using the Wilcoxon rank-sum test and the Wilcoxon signed rank test, respectively. Results show a slower mean rate of absorption, K-a, (0.12 vs. 0.15 min(-1), p = 0.03) and a longer time to reach maximum concentration, T-max, (28 vs. 23 minute, p < 0.01) for the ML compared with DS-Etoh beverage. The ML beverage resulted in a larger area under the BrAC-time curve compared with DS-Etoh beverage (8.4 vs. 6.8 min g/dl, p = 0.02). There was no difference in the subjective PD effects between the 2 beverages. Results show that exposure to ethanol following the consumption of ML beverages is different compared to that following nonmalt beverages in African-Americans. These differences may be related to nonfermented by-products present in commercially available ML products. These PK differences do not appear to result in significant perceived alcohol PD changes, nor are they related to ADH genotype.

Tudhope G. Alcohol Awareness Manual. London: Haynes, 2006

This book is modeled after an extensive series of workshop manuals the publisher produces for hundreds of cars and motorcycles round the world. Those manuals specialize in helping people carry out the necessary maintenance and repairs. The same format is adopted for this drinker's manual. It describes the hazards of excessive drinking, and effects of alcohol on the body, and while potentially of lesser value to the personal with alcohol dependence, it covers many of the issues pertinent to anyone who uses alcohol.

Verster JC. The alcohol hangover: A puzzling phenomenon. (review). Alcohol and Alcoholism 43(2): 124-126, 2008. (17 refs.)

The alcohol hangover develops when blood alcohol concentration (BAC) returns to zero and is characterized by a feeling of general misery that may last more than 24 h. It comprises a variety of symptoms including drowsiness, concentration problems, dry mouth, dizziness, gastro-intestinal complaints, sweating, nausea, hyper-excitability, and anxiety. The alcohol hangover is an intriguing issue since it is unknown why these symptoms are present after alcohol and its metabolites are eliminated from the body. Although numerous scientific papers cover the acute effects of alcohol consumption, researchers largely neglected the issue of alcohol hangover. This lack of scientific interest is remarkable, since almost everybody is familiar with the unpleasant hangover effects that may arise the day after an evening of excessive drinking, and with the ways these symptoms may affect performance of planned activities. Many people favour the (unproven) popular belief that dehydration is the main cause of alcohol hangover symptoms. More recently the potential role of the immune sytem and the cytokines is reviewed.

Wolf A; Bray GA; Popkin BM. A short history of beverages and how our body treats them. Obesity Reviews 9(2): 151-164, 2008. (77 refs.)

Numerous studies have demonstrated that beverages containing sugar, high fructose corn syrup (HFCS) or alcohol are handled differently by the body than when sugar or HFCS are incorporated in solid foods and as a result the overall caloric intake from solid food does not adjust to account for the calories in these beverages. A consideration of our evolutionary history may help to explain our poor compensatory response to calories from fluids. This paper reviews the history of eight important beverages: milk, beer, wine, tea, coffee, distilled alcoholic beverages, juice and soft drinks. We arrive at two hypotheses. First, humans may lack a physiological basis for processing carbohydrate or alcoholic calories in beverage because only breast milk and water were available for the vast majority of our evolutionary history. Alternatives to those two beverages appeared in the human diet no more than 11 000 years ago, but Homo sapiens evolved between 100,000 and 200,000 years ago. Second, carbohydrate and alcohol-containing beverages may produce an incomplete satiation sequence which prevents us from becoming satiated on these beverages.

Wurst FM; Dursteler-MacFarland KM; Auwaerter V; Ergovic S; Thon N; Yegles M et al. Assessment of alcohol use among methadone maintenance patients by direct ethanol metabolites and self-reports. Alcoholism: Clinical and Experimental Research 32(9): 1552-1557, 2008. (54 refs.)

Background: Heavy alcohol consumption may accelerate the progression of hepatitis C (HCV)-related liver disease and/or limit efforts at antiviral treatment. As most of the patients in methadone maintenance treatment (MMT) suffer from hepatitis C infection, this study was conducted to identify the alcohol intake among these patients at a Swiss Psychiatric University Clinic by self-reports and direct ethanol metabolites as biomarkers of ethanol consumption. Patients and Methods: A convenience sample of 40 MMT patients (15 women, 25 men; median age 39 years) of the total 124 patients was asked and consented to participate in this study. This sample was not different in age, gender distribution, and rate of hepatitis C infection from the total sample. The Alcohol Use Disorders Identification Test (AUDIT) and self-reported ethanol intake during the previous 7 days were assessed. In addition, ethyl glucuronide (EtG) in urine, and fatty acid ethyl esters (FAEEs) and EtG in hair were determined using LC-MS/MS and gas chromatograph/mass spectrometer. The limit of quantitation for UEtG, HEtG, and FAEEs were 0.1 mg/l, 2.3 pg/mg, and 0.1 ng/mg, respectively. Results: Fourteen participants reported abstinence from alcohol for the previous 7 days. AUDIT scores were >= 8 in 15 male and > 5 in 5 female participants. Direct ethanol metabolites were as follows (median, min, max, standard deviation): UEtG (19 positives; 9.91, 1.38 to 251, 62.39 mg/l); the values of HEtG were 17.65, 0 to 513, 105.62 pg/mg [in 2 cases no material, 8 abstinent (up to 7 pg/mg), 15 social drinkers (up to 50 g per day), and 15 excessive users (> 50/60 g/d)]. For the 13 cases, where enough material for additional determination of HFAEEs was available, the values were 0.32, 0 to 1.32, 0.44 ng/mg. Among the 30 HEtG-positive participants, 20 had not reported the corresponding ethanol intake using question 1 (frequency) and 2 (quantity) of the AUDIT. Of the 14 participants reporting no alcohol intake during the previous 7 days, 4 were UEtG-positive. HEtG and AUDIT correlated significantly (r = 0.622, p < 0.0001), but this was not the case for UEtG and self-reported ethanol intake during the previous 7 days. Conclusion: (1) HEtG identified 20 cases of daily ethanol intake of more than 20 g, that would have been missed by the sole use of question 1 (frequency) and 2 (quantity) of the AUDIT. (2) Using the total score of the AUDIT, HEtG confirmed 10 more cases positive for alcohol intake. (3) Episodic heavy drinking is with 22.5% more frequent than in general population, and (4) of the 14 participants who reported no alcohol intake during the previous 7 days, 4 were UEtG positive. Improved detection of alcohol consumption, which is hazardous or harmful in the context of HCV and opiate dependence, would allow for earlier intervention in this population which is at particular risk of liver disease and fatal respiratory-depressed overdose. The combined use of self-reports and direct ethanol metabolites seems promising.

Beulens JWJ; Rimm EB; Hendriks HFJ; Hu FB; Manson JE; Hunter DJ; Mukamal KJ. Alcohol consumption and type 2 diabetes: Influence of genetic variation in alcohol dehydrogenase. Diabetes 56(9): 2388-2394, 2007. (47 refs.)

OBJECTIVE-We sought to investigate whether a polymorphism I in the alcohol dehydrogenase 1c (ADH1C) gene modifies the association between alcohol consumption and type 2 diabetes. RESEARCH DESIGN AND METHODS-In nested case-control studies of 640 women with incident diabetes and 1,000 control subjects from the Nurses'Health Study and 383 men with incident diabetes and 382 control subjects from the Health Professionals Follow-Up Study, we determined associations be- tween the ADH1C polymorphism, alcohol consumption, and diabetes risk. RESULTS-Moderate to heavy alcohol consumption (>5 g/day for women and >10 g/day for men) was associated with a decreased risk of diabetes among women (odds ratio [OR] 0.45 [95% CI 0.33-0.63]) but not men (1.08 [0.67-1.75]). ADH1C genotype modified the relation between alcohol consumption and diabetes for women (P-interaction = 0.02). The number of ADH1C*2 alleles, related to a slower rate of ethanol oxidation, attenuated the lower risk of diabetes among women consuming >= 5 g alcohol/day (P-trend = 0.002). These results were not significant among men. Results were similar in pooled analyses (P-interaclon = 0.02) with ORs for diabetes among moderate drinkers of 0.44 (95% CI 0.21-0.94) in ADHlC*1 homozygotes, 0.65 (0.39-1.06) for heterozygotes, and 0.78 (0.50-1.22) for ADH1C*2 homozygotes compared with those for ADH1C*l homozygote abstainers (P-trend = 0.02). CONCLUSIONS-ADH1C genotype modifies the association between alcohol consumption and diabetes. The ADH1C*2 allele, related to a slower oxidation rate, attenuates the lower diabetes risk among moderate to heavy drinkers. This suggests that the association between alcohol consumption and diabetes may be causal but mediated by downstream metabolites such as acetate rather than ethanol itself.

Bongaerts BWC; de Goeij AFPM; van den Brandt PA; Weijenberg MP. Alcohol and the risk of colon and rectal cancer with mutations in the K-ras gene. Alcohol 38(3): 147-154, 2006. (24 refs.)

The first metabolite of alcohol, acetaldehyde, may trigger replication errors and mutations in DNA, which may predispose to developing colorectal cancer (CRC). In a prospective study on colon and rectal cancer, we investigated the following hypotheses: alcohol consumption is associated with an increased risk of mutations in the K-ras oncogene, and beer consumption is associated with an increased risk of G A mutations in this gene. Therefore, we studied the associations between consumption of alcohol and alcoholic beverages and the risk of CRC without and with specific K-ras gene mutations. In 1986, 120,852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer. The case-cohort approach was used for data processing and analyses. After 7.3 years of follow-up, excluding the first 2.3 years, complete data from 4,076 subcohort members, 428 colon and 150 rectal cancer patients, were available for data analyses. Incidence rate ratios (RRs) and corresponding 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models. Compared to abstaining, a total alcohol consumption of 30.0 g/day and more was associated with the risk of colon and rectal cancer with and without a K-ras mutation in both men and women. Independent from alcohol intake, liquor consumption when compared to nonliquor consumption was associated with an increased risk of rectal cancer with a wild type K-ras in men (RR: 2.25, 95% CI: 1.0-5.0). Beer consumption was not clearly associated with the risk of colon and rectal tumors harboring G -> A mutations in the K-rax gene in men. This association could not be assessed in women because of sparse beer consumption. In conclusion, alcohol does not seem to be involved in predisposing to CRC through mutations in the K-ras gene, and specifically beer consumption is not associated with colon and rectal tumors harboring a G -> A mutation.

Bradford BU; Karnitsching J; Powell LL; Garbutt JC. Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol. Alcohol 41(4): 263-270, 2007. (35 refs.)

Rapid changes in rates of ethanol metabolism in response to acute ethanol administration have been observed in animals and humans. To examine whether this phenomenon might vary by risk for alcoholism, 23 young men with a positive family history of alcoholism (family history positive [FHP]) were compared to 15 young men without a family history of alcoholism (family history negative [FHN]). Rates of ethanol metabolism were measured in all subjects first after an initial ethanol dose (0.85 g/kg) and then, several hours later, a second dose (0.3 g/kg), and the two rates were compared. The two groups of subjects were similar in their histories of ethanol consumption. FHP subjects demonstrated faster initial rates of ethanol metabolism, 148 36 mg/kg/h, compared to FHN subjects, 124 18 mg/kg/h, P = .01. However, FHN subjects increased their rate of metabolism by 10 +/- 27% compared to a decrease of -15 +/- 24% in FHP subjects, P = .007. Fifty-two percent of the FHP and none of the FHN subjects exhibited a decline in metabolic rate of 20% or more, P = .0008. Since a significant proportion of FHP subjects exhibited a decrease in the second rate of ethanol metabolism, these preliminary data might help to partly explain why FHP individuals differ in their sensitivity to ethanol and are more likely to develop alcohol dependence.

Bradford BU; Rusyn I. Swift increase in alcohol metabolism (SIAM): Understanding the phenomenon of hypermetabolism in liver. Alcohol 35(1): 13-17, 2005. (35 refs.)

The swift increase in alcohol metabolism (SIAM) is a phenomenon defined as a rapid increase in hepatic respiration and alcohol metabolism after administration of a bolus dose of alcohol. Continuous exposure to alcohol is known to produce adaptive changes in liver alcohol and oxygen metabolism. A considerable burst of hepatic respiration can also occur after administration of a single large dose of alcohol and results in a near doubling of alcohol metabolism, a high demand for oxygen, and downstream or pericentral hypoxia. These dramatic changes in rates of alcohol metabolism and tissue concentrations of oxygen are not due to induced enzyme activity in liver. This phenomenon depends on activation of mitochondrial function, an increase in co-factor supply for nicotinamide adenine dinucleotide-dependent alcohol metabolism, depletion of glycogen reserves, liberation of fatty acids through activation of an adrenergic response to alcohol providing substrate for catalase, and activation of Kupffer cells, the hepatic resident macrophages responsible for production of cytokines and prostaglandins. An understanding of the mechanisms of hypermetabolism in liver can have vital ramifications for knowledge of both alcohol-related and alcohol-unrelated liver injury because hypoxia that is a result of hypermetabolism can compound effects of pharmaceuticals and environmental agents on the liver. Swift increase in alcohol metabolism is an excellent example of the complexity of cell-cell interactions in liver and extrahepatic regulation of biochemical and molecular events in this organ, and this important phenomenon shall be considered in studies of liver disease and biochemistry.

Castro GD; de Castro CR; Maciel ME; Fanelli SL; de Ferreyra EC; Gomez MID et al. Ethanol-induced oxidative stress and acetaldehyde formation in rat mammary tissue: Potential factors involved in alcohol drinking promotion of breast cancer. Toxicology 219(1-3): 208-219, 2006. (60 refs.)

Recent studies from our laboratory provided evidence that part of the carcinogenic effects of ethanol consumption might be related to its in situ metabolism at cytosolic and microsomal levels, to the mutagen acetaldehyde and to hydroxyl and 1-hydroxyethyl radicals. In this work, we report on our experiments where Sprague-Dawley female rats were exposed to the standard Lieber & De Carli diet for 28 days. We observed: the induction of the (xanthineoxidoreductase mediated) cytosolic and microsomal (lipoxygenase mediated) pathways of ethanol metabolism; promotion of oxidative stress as shown by increased formation of lipid hydroperoxides; delay in the t-butylhydroperoxide induced chemiluminiscence, and a significant decrease in protein sulfhydryls. In addition, the epithelial cells showed ultrastructural alterations consisting of markedly irregular nuclei, with frequent invaginations at the level of the nuclear envelope, condensation of chromatin around the inner nuclear membrane, and marked dilatation of the nuclear pores showing filamentous material exiting to the cytoplasm. In conclusion, the presence in mammary epithelial cells of cytosolic and microsomal pathways of ethanol bioactivation to carcinogenic and to tumorigenic metabolites might play a role in alcohol promotion of breast cancer.

Chai YG; Oh DY; Chung EK; Kim GS; Kim L; Lee YS et al. Alcohol and aldehyde dehydrogenase polymorphisms in men with type I and type II alcoholism. American Journal of Psychiatry 162(5): 1003+, 2005. (7 refs.)

Objective: The authors examined the genetic polymorphisms of alcohol dehydrogenase 2 and 3 (ADH2 and ADH3) and aldehyde dehydrogenase (ALDH2) in patients diagnosed as having Cloninger's type I or type II alcoholism. Method: Seventy-two alcoholic men and 38 nonalcoholic, healthy men were tested for the distribution of genotypes and alleles of ADH2, ADH3, and ALDH2. Forty-eight of the alcoholic men had type I alcoholism, and 24 had type II alcoholism. Results: The frequencies of ADH2* 1 and ADH3* 2 alleles were significantly higher in men with type II alcoholism than in men with type I alcoholism and healthy men. The frequency of the ALDH2* 1 allele was significantly higher in men with alcohol dependence than in healthy men. Conclusions: The genetic characteristics of alcohol dehydrogenases in men with type I alcoholism were similar to those of healthy men, and the genetic characteristics of aldehyde dehydrogenase in men with type I alcoholism were similar to those of men with type II alcoholism. These findings suggest that the genetic characteristics of alcohol metabolism in type I alcoholism fall between nonalcoholism and type II alcoholism.

Chen YJ; Chen C; Wu DC; Lee CH; Wu CI; Lee JM et al. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisins on esophageal cancer risks. International Journal of Cancer 119(12): 2827-2831, 2006. (32 refs.)

In our previous study, we found that polymorphisms of alcohol and aldehyde dehydrogenase (ADH1B and ALDH2) are important risks for esophageal squamous cell carcinoma in a Taiwanese population. In this study, we increased the sample size to investigate the modifying effect of lifetime alcohol consumption on the association between ADH1B and ALDH2 genotypes and the risks of esophageal cancer. A multicenter hospital-based case-control study was conducted between August 2000 and June 2004. Three hundred and thirty newly-diagnosed esophageal squamous cell carcinoma patients and 592 controls were recruited from National Taiwan University Hospital in Taipei and Kaohsiung Veterans General Hospital and Kaohsiung Medical University Hospital in Kaohsiung, Taiwan. Controls were matched to the case patients by gender and age within 4 years (case:control = 1:1-4). Polymorphisms of ADH1B and ALDH2 were genotyped by the method of PCR-RFLP. Individuals with ADH1B*1/*1 genotype had a 3.99-fold risk (95% CI = 2.13-7.48) of developing esophageal cancer, compared with those with ADH1B*2/*2 genotype, after adjusted for appropriate covariates. Individuals with ALDH2*1/*2 and ALDH2*2/*2 had 4.99-fold risk (95% CI = 3.11-7.99) and 4.24-fold risk (95% CI = 1.52-11.84), respectively, of developing esophageal cancer, compared with those with ALDH2*1/*1, after adjusted for appropriate covariates. We also found a modifying effect of lifetime alcoholic consumption on the association between genotypes of ADH1B and ALDH2 on esophageal cancer risk. These results suggest that ADH1B and ALDH2 polymorphisms play a pivotal role on esophageal cancer and that the effect of these polymorphisms was modified by the amount of alcohol consumed.

Cichoz-Lach H; Partycka J; Nesina I; Celinski K; Slomka M; Wojcierowski J. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Scandinavian Journal of Gastroenterology 42(4): 493-498, 2007. (40 refs.)

Objective. To investigate the effects of ADH and ALDH gene polymorphism on the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals. Material and methods. We determined the allele and genotype of ADH2, ADH3 and ALDH2 in 198 subjects: 57 with alcohol cirrhosis, 44 with alcohol chronic pancreatitis and 43 "healthy alcoholics"; 54 healthy non-drinkers served as controls. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method on white cell DNA. Results. In the population examined the ADH2*1 allele frequency was 97.97%. The tests did not show the ADH2*3 allele. The ADH3*1 allele frequency was 57.07%. The ADH2*1 and the ADH3*1 alleles were statistically more common among patients who abuse alcohol in comparison with the controls. The ADH2*2 allele was not detected in any of the patients with chronic alcohol pancreatitis. The ADH2*1/*1 and the ADH3*1/*1 genotypes were statistically significantly more common among the patients who abuse alcohol than in the control group. All patients were ALDH2*1/*1 homozygotic. Patients with the ADH3*1 allele and the ADH3*1/*1 genotype started to abuse alcohol significantly earlier in comparison to the patients with the ADH3*2 allele and the ADH3*2/*2 genotype. Conclusions. In the Polish population examined, the ADH3*1 allele and the ADH3*1/*1 genotype are conducive to the development of alcoholism, alcohol liver cirrhosis and alcohol chronic pancreatitis. However, the ADH2*2 allele is likely to protect against these conditions. Genetic polymorphism of ALDH2 shows no correlation with alcohol addiction or alcohol cirrhosis and alcohol chronic pancreatitis. The ADH3*1 allele and the ADH3*1/*1 genotype are conducive to alcohol abuse starting at a younger age.

Clemens DL. Use of cultured cells to study alcohol metabolism. Alcohol Research & Health 29(4): 291-295, 2006. (19 refs.)

The use of cells grown in the laboratory (i.e., cultured cells) in alcohol research has many advantages. Among these are the ability to investigate individual metabolic pathways, the ability to precisely control exposure to ethanol and its metabolites in the absence of confounding variables, and the uniformity of genetically identical (i.e., clonal) cell lines. Additionally, because of the cost and relative ease of culturing large quantities of cells, many more experimental replicas may be performed to confirm findings. As described in this article, the use of cultured cells has contributed greatly to the understanding of the mechanisms by which alcohol metabolism affects cells and ultimately results in alcoholic liver disease.

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Cook TAR; Luczak SE; Shea SH; Ehlers CL; Carr LG; Wall TL. Associations of ALDH2 and ADH1B genotypes with response to alcohol in Asian Americans. Journal of Studies on Alcohol 66(2): 196-204, 2005. (65 refs.)

Objective: Individuals with alcohol dependence are less likely to possess variant alleles of the alcohol-metabolizing genes, aldehyde dehydrogenase (ALDH2*2) and alcohol dehydrogenase (ADHIB*2), than non-alcohol-dependent controls. It is hypothesized that the mechanism through which these alleles protect against alcohol dependence is by causing elevations in acetaldehyde, which in turn cause an increased response to alcohol. Previous research has shown that individuals with ALDH2*2 demonstrate enhanced reactions to alcohol compared with those without this genetic variant, but evidence that ADHIB*2 is associated with a greater alcohol response is mixed. This study was designed to determine whether the ADHIB genotype is associated with more intense reactions to alcohol after controlling for the ALDH2 genotype. Method: Participants (N = 101) were Asian American college students. Each was evaluated using objective and subjective measures before and after ingestion of alcohol and placebo beverages. Results: Participants with the ALDH2*1/*2 and ALDH2*2/*2 genotypes were more likely to experience vomiting following ingestion of the alcohol beverage than those with the ALDH2*1/*1 genotype. Participants with the ALDH2*1/*2 genotype also had greater pulse-rate increases, observed flushing ratings, and subjective feelings of intoxication 30 minutes after ingestion of alcohol than participants with the ALDH2*1/*1 genotype, despite equivalent blood alcohol concentration (BAC) measurements. Among participants with the ALDH2*1/*1 genotype, there were no additional effects of the ADHIB genotype on any measures of response to alcohol. Among participants with the ALDH2*1/*2 genotype, those with the ADHIB*2/*2 genotype were more likely to experience alcohol-induced vomiting and to report feeling less "great overall" 30 minutes after ingestion of alcohol than those with the ADHIB*1/*2 genotype. Conclusions: These findings are consistent with the hypothesis that there is an additional effect of ADHIB*2 on level of response to alcohol, but only among individuals with the ALDH2*1/*2 genotype.

Dettling A; Fischer F; Bohler S; Ulrichs F; Skopp G; Graw M et al. Ethanol elimination rates in men and women in consideration of the calculated liver weight. Alcohol 41(6): 415-420, 2007. (52 refs.)

The purpose of the study was to examine gender differences on the pharmacokinetics of ethanol. Sixty-eight healthy men and 64 healthy women with normal body mass indexes received between 0.79 and 0.95 g ethanol/kg body weight in the form of their choice after they had eaten a "typical" breakfast. The aimed concentration for both genders was a blood alcohol concentration C-0 of 0.104 g/dl. Blood samples in the elimination phase were taken in 10- to 20-min intervals beginning after completion of absorption. The maximum blood ethanol concentration was 0.0819 +/- 0.0184 g/dl for women and 0.0841 +/- 0.0155 g/dl for men. The hourly ethanol elimination rate, calculated over a linear function, in blood of 0.0179 +/- 0.0030 g/dl/h in women was significantly higher than the 0.0159 +/- 0.0029 g/dl/h for men (P <.0001). In relation to the liver weight, the hourly elimination rates were 5.008 +/- 0.678 g/kg liver/h for women and 4.854 +/- 0.659 g/kg liver/h for men, and were not statistically significant. The different liver masses as calculated in relation to the distribution volume account for the differing ethanol elimination rates between men and women.

Edenberg HJ. The genetics of alcohol metabolism - Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Research & Health 30(1): 5-13, 2007. (45 refs.)

The primary enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both enzymes occur in several forms that are encoded by different genes; moreover, there are variants (i.e., alleles) of some of these genes that encode enzymes with different characteristics and which have different ethnic distributions. Which ADH or ALDH alleles a person carries influence his or her level of alcohol consumption and risk of alcoholism. Researchers to date primarily have studied coding variants in the ADH1B, ADH1C, and ALDH2 genes that are associated with altered kinetic properties of the resulting enzymes. For example, certain ADH1B and ADH1C alleles encode particularly active ADH enzymes, resulting in more rapid conversion of alcohol (i.e., ethanol) to acetaldehyde; these alleles have a protective effect on the risk of alcoholism. A variant of the ALDH2 gene encodes an essentially inactive ALDH enzyme, resulting in acetaldehyde accumulation and a protective effect. It is becoming clear that noncoding variants in both ADH and ALDH genes also may influence alcohol metabolism and, consequently, alcoholism risk; the specific nature and effects of these variants still need further study.

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Edenberg HJ; Xuei XL; Chen HJ; Tian HJ; Wetherill LF; Dick DM et al. Association of alcohol dehydrogenase genes with alcohol dependence: A comprehensive analysis. Human Molecular Genetics 15(9): 1539-1549, 2006. (54 refs.)

Linkage evidence indicated that gene(s) located on chromosome 4q, in the region of the alcohol dehydrogenase (ADH) genes, affected risk for alcoholism. We genotyped 110 single nucleotide polymorphisms (SNPs) across the seven ADH genes and analyzed their association with alcoholism in a set of families with multiple alcoholic members, using the pedigree disequilibrium test. There was strong evidence that variations in ADH4 are associated with alcoholism: 12 SNPs were significantly associated. The region of strongest association ran from intron 1 to 19.5 kb beyond the 3' end of the gene. Haplotype tag SNPs were selected for the block in the ADH4 gene that provided evidence of association and subsequently used in association analysis; the haplotype was significantly associated with alcoholism (P=0.01) There was weaker evidence that variations in ADH1A and ADH1B might also play a role in modifying risk. Among African-Americans, there was evidence that the ADH1B*3 allele was protective.

Ehlers CL. Variations in ADH and ALDH in southwest California Indians. Alcohol Research & Health 30(1): 14-17, 2007. (17 refs.)

Native Americans as a group have the highest rates of alcohol-related deaths of all ethnicities in the United States, however, it remains unclear how and why a greater proportion of individuals in some Native American communities develop alcohol-related problems and alcohol use disorders (AUDs). One potential factor that can influence responses to alcohol are variations in alcohol-metabolizing enzymes. Researchers have analyzed the frequencies of variants in the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in some Native American populations. So far the studies have yielded no evidence that an ALDH2 variant, which has shown protective effects in other populations, is found in either American Indians or Alaska Natives. A variant of the ALDH1 enzyme that is encoded by the ALDH1A1 *2 allele, however, was found in a small proportion of a group of Southwest California Indians and had a protective effect against alcoholism in that population. Furthermore, a variant of the ADH1B enzyme that is encoded by the ADH1B *3 allele was found in a similar proportion of Southwest California Indians and also was associated with a protective effect. However, these findings do not explain the high prevalence of alcoholism in the tribes investigated.

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Eng MY; Luczak SE; Wall TL. ALDH2, ADH1B, and ADH1C genotypes in Asians: A literature review. Alcohol Research & Health 30(1): 22-27, 2007. (31 refs.)

Variants of three genes encoding alcohol-metabolizing enzymes, the aldehyde dehydrogenase gene ALDH2 and the alcohol dehydrogenase genes ADH1B and ADH1C, have been associated with reduced rates of alcohol dependence. The genotype prevalence of these genes varies in general samples of different Asian ethnic groups. The ALDH2*2 allele appears to be most prevalent in Chinese-American, Han Chinese and Taiwanese, Japanese, and Korean samples. Much lower rates have been reported in Thais, Filipinos, Indians, and Chinese and Taiwanese aborigines. ADH1B*2 is highly prevalent among Asians, with the exception of Indians. ADH1C*1 also is highly prevalent in Asians, but has only been examined in a few studies of Chinese and Korean samples.

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Fisher SJ; Lee IJ; Swaan PW; Eddington ND. Evaluation of the effect of ethanol's toxic metabolite acetaldehyde on the gastrointestinal oligopeptide transporter, PEPT1: In vitro and in vivo studies. Alcoholism: Clinical and Experimental Research 32(1): 162-170, 2008. (57 refs.)

Background: The effects of alcohol consumption and its subsequent metabolism on drug transport, absorption and pharmacokinetics are poorly understood. This study examines the effects of the ethanol metabolite, acetaldehyde, on the clinically relevant drug transporter, PEPT1. The metabolism of ethanol and the following acetaldehyde formation is thought to modulate the uptake capacity of PEPT1 within the gastrointestinal tract for a variety of clinically important peptidomimetic drug compounds. Methods: Glycylsarcosine ([H-3]-GlySar), a nonhydrolysable PEPT1 specific substrate was used in our studies. In vitro uptake studies were performed in the Caco-2 and Chinese hamster ovary (CHO)-hPEPT1 cell models, measuring cellular uptake of labeled compound against increasing levels of unlabeled compound in the presence of acetaldehyde. In vivo absorption of [H-3]-GlySar was measured in male Sprague-Dawley rats that were treated with oral dose of ethanol/disulfiram (5 g/kg / 100 mg/kg) for 6 days. These results were compared to control rats treated with saline, ethanol alone or disulfiram alone. Results: In vitro uptake of [H-3]-GlySar in CHO-hPEPT1 cells treated with 1 mM acetaldehyde was significantly decreased (p < 0.05) as compared to untreated controls. The uptake of [H-3]-GlySar in Caco-2 cell monolayers treated with 1 mM acetaldehyde was also significantly decreased as compared to the untreated control cells. In vivo absorption of [H-3]-GlySar in ethanol treated rats, as measured by AUC(0-12 hours) were decreased by approximately 50% versus the control rat group. Conclusion: The effects of acetaldehyde due to consumption of ethanol on the uptake and bioavailability of therapeutic drug compounds transported by the PEPT1 oligopeptide transporter have not been documented. In the present studies, we demonstrate that acetaldehyde significantly modulates PEPT1 function and, thereby, affects drug bioavailability. To our best knowledge, this is the first report on the effects of an ethanol metabolite on substrate absorption in the gastrointestinal tract, rather than interactions in the liver, which is an under-represented area of research in alcohol pathophysiology.

Gemma S; Vichi S; Testai E. Metabolic and genetic factors contributing to alcohol induced effects and fetal alcohol syndrome. (review). Neuroscience and Biobehavioral Reviews 31(2): 221-229, 2007. (53 refs.)

Alcohol-related damages on newborns and infants include a wide variety of complications from facial anomalies to neurodevelopmental delay, known as fetal alcohol syndrome (FAS). However, only less than 10% of women drinking alcohol during pregnancy have children with FAS. Understanding the risk factors increasing the probability for newborn exposed in utero to alcohol to develop FAS is therefore a key issue. The involvement of genetics as a one risk factor in FAS has been suggested by animal models and by molecular epidemiological studies on different populations, bearing allelic variants for those enzymes, such as ADH e CYP2E1, involved in ethanol metabolism. Indeed, one of the major factors determining the peak blood alcohol exposure to the fetus is the metabolic activity of the mother, in addition to placental and fetal metabolism, explaining, at least partially, the risk of FAS. The different rates of ethanol metabolism may be the result of genetic polymorphisms, the most relevant of which have been described in the paper.

Goldman D; Oroszi G; O'Malley S; Anton R. COMBINE genetics study: The pharmacogenetics of alcoholism treatment response: Genes and mechanisms. Journal of Studies on Alcohol Supplement 15: 56-64, 2005. (61 refs.)

Objective: Partial efficacy of treatment and differences in adverse events across individuals are a challenge and an opportunity in the treatment of alcoholism. Individuation of therapy and understanding origins of differential treatment response may require identification of inherited functional variants of genes. The neurobiology of reward, executive cognitive function, anxiety and dysphoria have been identified as critical domains that may have a genetic basis that could predict treatment response. Method: The COMBINE Study presents a unique opportunity to evaluate specific genetic loci (markers) that affect neurobiology central to addiction and extended withdrawal. The study also addresses variation in drug metabolism and action. Candidate genetic markers are selected for study based on functionality and abundance. Results: COMT Val158Met is a common (minor allele frequency 0.42), functional, catecholamine-metabolizing enzyme polymorphism with threefold relevance. Val158Met alters executive cognitive function, stress and anxiety responses and brain endogenous opioid function. OPRM1 Asn40Asp is a common (minor allele frequency 0.10), functional polymorphism of the mu-opioid receptor, which may serve as a gatekeeper molecule in naltrexone's actions and was recently reported to affect naltrexone response. HTTLPR (minor allele frequency 0.40) alters serotonin transporter function to affect anxiety, dysphoria and obsessional behavior, which are assessed in COMBINE and may be related to relapse and addictive behavior. Conclusions: All genetic testing is consented through a separate human research protocol, and the testing is conducted nonclinically, confidentially and apart from the clinical record to protect human research participants who have volunteered for this aspect of COMBINE.

Grassi MC; Cioce AM; Giudici FD; Antonilli L; Nencini P. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: A pilot study. Pharmacological Research 55(2): 117-121, 2007. (38 refs.)

Cocaine abusers frequently report taking the drug in association with alcohol. This combined intake leads to the synthesis of cocaethylene, an active metabolite with effects similar to those of cocaine, but more prolonged. Since pharmacological effects of cocaethylene may partially account for the habit of cocaine abusers to take the drug in combination with ethanol, a main therapeutic goal in these patients should be making body fluids negative for cocaethylene. This randomized controlled open study conducted on 12 subjects co-abusers of cocaine and alcohol, evaluates the efficacy of a 12-week pharmacological treatment with Disulfiram (DIS) 400 mg daily or Naltrexone (NTX) 50 mg daily associated with Cognitive Behaviour Therapy (CBT), as compared to CBT alone, in terms of: (i) stay in treatment; (ii) drug-free urinalyses for cocaine and cocaethylene; (iii) reduction of alcohol and cocaine craving. Data presented in this study are restricted to the first 4 weeks of treatment when all the enrolled subjects were still available for examination. In fact, of the 12 subjects enrolled in the study only 4 (33%) completed the 12-week treatment. Of these, three were in the CBT group and one in the NTX/CBT group. Results show that CBT treated subjects remained in treatment longer than those assigned to either DIS/CBT or NTX/CBT therapies. However, during the first 4 weeks of treatment, CBT-group urine tested positive almost always for both cocaine and cocaethylene. In contrast, both DIS/CBT and NTX/CBT treatments were associated to a statistically significant reduction, of positive urinalysis for both cocaine and cocaethylene, with respect to CBT alone. Moreover, across the first 4 weeks of treatment DIS/CBT and NTX/CBT treated subjects maintained lower scores at Visual Analogue Scales (VAS) for both cocaine and alcohol craving than subjects receiving CBT alone. This pilot study suggests that the transient efficacy of pharmacological treatments in maintaining subjects drug free, does not add to the capability of CBT to retain them in treatment.

Hendershot CS; MacPherson L; Myers MG; Carr LG; Wall TL. Psychosocial, cultural and genetic influences on alcohol use in Asian American youth. Journal of Studies on Alcohol 66(2): 185-195, 2005. (59 refs.)

Objective: Environmental and cultural factors, as well as a genetic variant of the aldehyde dehydrogenase gene (the ALDH2*2 allele) have been identified as correlates of alcohol use among Asian Americans. However, concurrent examination of these variables has been rare. The present study assessed parental alcohol use, acculturation and ALDH2 gene status in relation to lifetime, current and heavy episodic drinking among Chinese and Korean American undergraduates. Method: Participants (N = 428, 51% women; 52% Chinese American, age 18-19 years) were first-year college students in a longitudinal study of substance use initiation and progression. Data were collected via structured interview and self-report, and participants provided a blood sample for genotyping at the ALDH2 locus. Results: Gender, parental alcohol use and acculturation significantly predicted drinking behavior. However, none of the hypothesized moderating relationships were significant. In contrast with previous studies, ALDH2 gene status was not associated with alcohol use. Conclusions: Results indicate that although the variables examined influence alcohol use, moderating effects were not observed in the present sample of Asian American college students. Findings further suggest that the established association of ALDH2 status and drinking behavior in Asians may not be evident in late adolescence. It is possible that ALDH2 status is associated with alcohol consumption only following initiation and increased drinking experience.

Hey H; Schmedes A; Nielsen AA; Winding P; Gronbaek H. Effects of five different alcoholic drinks on patients with Crohn's disease. Scandinavian Journal of Gastroenterology 42(8): 968-972, 2007. (16 refs.)

Objective. Many patients with Crohn's disease ( CD) complain of abdominal discomfort after alcohol intake. The aim of the present study was to investigate the effect of ethanol and sugar content in five different alcoholic drinks on abdominal discomfort in patients with CD. Material and methods. In a crossover study, two weeks apart, 12 healthy individuals and 20 patients with CD in remission consumed randomly red wine, white wine, Smirnoff Ice, Elephant Beer and pure ethanol. Blood samples were obtained for determination of serum ethanol and plasma glucose at 0, 30, 60, 90, 120 and 180 min. A self-reported pain symptom score was used. Results. There was no difference between CD patients and healthy individuals in the area under the curve (AUC) for the ethanol concentration after intake of the five different drinks. The plasma AUC for glucose in the CD patients after intake of Smirnoff Ice and Elephant beer was significantly increased (p < 0.05) in comparison with that in the remaining three alcoholic drinks. Abdominal pain manifestations were significantly more pronounced in CD patients following intake of Smirnoff Ice and Elephant beer, with their higher sugar concentration, compared with intake of the remaining three drinks (p < 0.05). Conclusions. The present study shows no difference in alcohol absorption between CD patients and controls. The alcoholic drinks Smirnoff Ice and Elephant beer have an increased effect on self-reported abdominal pain in CD patients, probably due to the high sugar content in these drinks.

Hines LA; Hunter DJ; Stampfer MJ; Spiegelman D; Chu NF; Rifai N et al. Alcohol consumption and high-density lipoprotein levels: The effect of ADH1C genotype, gender and menopausal status. Atherosclerosis 182(2): 293-300, 2005. (27 refs.)

We previously demonstrated that a functional polymorphism in alcohol dehydrogenase type 1C (ADH1C, also known as ADH3) modifies the association between moderate alcohol consumption and high-density lipoprotein (HDL) levels and risk of myocardial infarction among older men. In this study, we investigated the effect of the ADH1C gamma(1) and gamma(2) alleles on the relationship between alcohol consumption and HDL levels among four populations with varied exposure to endogenous and exogenous estrogens: premenopausal women, middle-to-older aged men, postmenopausal women currently using postmenopausal hormones (PMH) and postmenopausal women not currently using PMH. We observed an interaction between moderate alcohol consumption and ADH1C genotype on HDL level that was similar among middle-to-older aged men and postmenopausal women not using PMH. Among the moderate drinkers (approximately a half a drink per day for women and a full drink per day for men), there was a significant 5.3 mg/dL (P = 0.02) higher level of multivariate adjusted HDL level comparing the gamma(2) homozygotes (slow oxidizers) to the gamma(1) homozygotes (fast oxidizers). This interaction was not present among premenopausal women or postmenopausal women using PMH, who had higher overall HDL levels irrespective of alcohol consumption. Our results confirm that ADH1C genotype modifies the association between alcohol consumption and HDL levels among men and postmenopausal women not using PMH who drink moderately. However, this was not observed among individuals with estrogen-elevated HDL levels, specifically premenopausal women and postmenopausal women taking PMH, suggesting that these populations may benefit less from alcohol consumption with respect to coronary heart disease.

Hiraki A; Matsuo K; Wakai K; Suzuki T; Hasegawa Y; Tajima K. Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Science 98(7): 1087-1091, 2007. (22 refs.)

Alcohol consumption is a strong risk factor for squamous cell carcinoma of the head and neck (SCCHN). The genetic polymorphisms aldehyde dehydrogenase2 (ALDH2) Glu487Lys and alcohol dehydrogenase 2 (ADH2) His47Arg, which have a strong impact on alcohol metabolism, are common in the Japanese population. To clarify the significance of these polymorphisms in SCCHN carcinogenesis, we conducted a matched case-control study with 239 incident SCCHN subjects and 716 non-cancer controls. Both ADH2 Arg/Arg and ALDH2 Glu/Lys were found to be independently associated with increased risk, with odds ratios (OR) of 2.67 (95% confidence interval [CI] 1.51-4.57) and 1.66 (95% CI 1.20-2.31), respectively. Further, compared with subjects having both ADH2 His/His and ALDH2 Glu/Glu, the adjusted OR and its 95% CI for those with both ADH2 Arg/Arg and ALDH2 Glu/Lys was 5.00 (2.32-10.71) in all subjects. This combination effect was evident in heavy drinkers (OR 11.3, 95% CI 2.97-43.3) but not in moderate or non-drinkers. Statistically significant gene-environment interactions between the two polymorphisms and drinking level were seen (ADH2 P = 0.035, ALDH2, P = 0.013). Furthermore, we also found a statistically significant gene-gene interaction between the two polymorphisms (P = 0.042). In conclusion, this case-control study showed a significantly increased risk of SCCHN in subjects with the ADH2 Arg/Arg and ALDH2 Glu/Lys polymorphisms in a Japanese population. In addition, our results also demonstrated that this risk was associated with significant gene-gene interactions between ADH2 and ALDH2 polymorphisms, as well as gene-environment interactions between these polymorphisms and alcohol drinking.

Kapur BM; Vandenbroucke AC; Adamchik Y; Lehotay DC; Carlen PL. Formic acid, a novel metabolite of chronic ethanol abuse, causes neurotoxicity, which is prevented by folic acid. Alcoholism: Clinical and Experimental Research 31(12): 2114-2120, 2007. (73 refs.)

Background: Methanol is endogenously formed in the brain and is present as a congener in most alcoholic beverages. Because ethanol is preferentially metabolized over methanol (MeOH) by alcohol dehydrogenase, it is not surprising that MeOH accumulates in the alcohol-abusing population. This suggests that the alcohol-drinking population will have higher levels of MeOH's neurotoxic metabolite, formic acid (FA). FA elimination is mediated by folic acid. Neurotoxicity is a common result of chronic alcoholism. This study shows for the first time that FA, found in chronic alcoholics, is neurotoxic and this toxicity can be mitigated by folic acid administration. Objective: To determine if FA levels are higher in the alcohol-drinking population and to assess its neurotoxicity in organotypic hippocampal rat brain slice cultures. Methods: Serum and CSF FA was measured in samples from both ethanol abusing and control patients, who presented to a hospital emergency department. FA's neurotoxicity and its reversibility by folic acid were assessed using organotypic rat brain hippocampal slice cultures using clinically relevant concentrations. Results: Serum FA levels in the alcoholics (mean +/- SE: 0.416 +/- 0.093 mmol/l, n = 23) were significantly higher than in controls (mean +/- SE: 0.154 +/- 0.009 mmol/l, n = 82) (p < 0.0002). FA was not detected in the controls' CSF (n = 20), whereas it was > 0.15 mmol/l in CSF of 3 of the 4 alcoholic cases. Low doses of FA from 1 to 5 mmol/l added for 24, 48 or 72 hours to the rat brain slice cultures caused neuronal death as measured by propidium iodide staining. When folic acid (1 mu mol/l) was added with the FA, neuronal death was prevented. Conclusions: Formic acid may be a significant factor in the neurotoxicity of ethanol abuse. This neurotoxicity can be mitigated by folic acid administration at a clinically relevant dose.

Kravos M; Malesic I; Levanic S. Serum alcohol dehydrogenase levels in patients with mental disorders. Clinica Chimica Acta 361(1/2): 86-94, 2005. (26 refs.)

Alcohol dehydrogenase (ADH) was assessed in 81 patients admitted to hospital for treatment for alcohol dependence with or without liver cirrhosis, 20 patients with bipolar disorder treated with lithium carbonate and 41 patients with various mental disorders treated with psychopharmacologic agents. Testing the hypothesis of the arithmetic mean showed that in alcohol dependents the arithmetic mean of ADH activity (12.19 nkat/1 +/- 5.61) differs significantly from that in healthy subjects (4.45 nkat/1 +/- 2.31) and in the group with ethanol poisoning (6.24 nkat/1 +/- 3.65) there is none. In the group with bipolar disorder, treated with lithium (7.39 nkat/1 +/- 3.11) and, in the group of patients treated with psychiatric drugs because of various mental disorders (7.79 nkat/1 +/- 8.51), the differences are statistically significant. In our opinion, assessing ADH activity in the sera of alcohol dependents could be an additional marker advantageous to the diagnostics, course and monitoring of therapy in such patients. In the groups of patients with mental disorders treated with psychotropic drugs, the increased ADH activity was found to be a more sensitive marker for the detection of drug hepatotoxicity.

Lee SP; Chiang CP; Lee SL; Hsia YJ; Chuang TL; Lin JC et al. Immunochemical features in the classification of human alcohol dehydrogenase family. Alcohol 39(1): 13-20, 2006. (37 refs.)

Human alcohol dehydrogenase (ADH) constitutes a complex family with diversified functions. Rabbit antihuman class I, II, III, and IV ADH antisera were prepared and used as probes to compare cross-reactivity with the isozymes across classes by serniquantitative Western blotting and quantitative enzyme-linked immunosorbent assay (ELISA). The interclass cross-reactivities with the noncognate isozymes by ELISA, generally similar to 0-35%, appeared considerably lower than those of the intraclass cross-reactivities except with the class IV isozyme. The anti-ADH1B1, ADH1C1, and ADH3 antisera, but not the anti-ADH2, exhibited similar to 80% cross-reactivity with ADH4. The intraclass cross-reactivities among class I isozymes ADH1A, ADH1B1, and ADH1C1 with anti-ADH1B1 or anti-ADH1C1 antisera were similar to 90%. Immunohistochemistry detecting with class-specific antibodies for ADH1-4 isolated from the corresponding antisera demonstrated that ADH4 was the predominant isoform expressed in the basal and suprabasal layer of human esophagus mucosa, whereas it was virtually devoid in the adjacent squamous cell carcinoma. Thus, the setup is more valuable for scanning ADH expression at protein level in different tissues and under different conditions, and maybe not as a tool for classification.

Loh EW; Lane HY; Chen CH; Chang PS; Ku LW; Wang KHT. Glutamate decarboxylase genes and alcoholism in Han Taiwanese men. Alcoholism: Clinical and Experimental Research 30(11): 1817-1823, 2006. (49 refs.)

Objective: Glutamate decarboxylase (GAD), the rate-limiting enzyme in the synthesis of gamma-aminobutyric acid (GABA), may be involved in the development of alcoholism. This study examined the possible roles of the genes that code for 2 forms of GAD (GAD1 and GAD2) in the development of alcoholism. Method: An association study was conducted among 140 male alcoholic subjects meeting the DSM-III-R criteria for alcohol dependence and 146 controls recruited from the Han Taiwanese in community and clinical settings. Psychiatric assessment of drinking conditions was conducted using a Chinese version of the Schedules for Clinical Assessment in Neuropsychiatry. The SHEsis and Haploview programs were used in statistical analyses. Results: Nine single-nucleotide polymorphisms (SNPs) at the GAD1 gene were valid for further statistics. Between alcoholic subjects and controls, significant differences were found in genotype distributions of SNP1 (p=0.000), SNP2 (p=0.015), SNP4 (p=0.015), SNP5 (p=0.031), SNP6 (p=0.012), and SNP8 (p=0.004) and in allele distributions of SNP1 (p=0.001), SNP2 (p=0.009), and SNP8 (p=0.009). Permutation tests of SNP1, SNP2, and SNP8 demonstrated significant differences in allele frequencies but not in 2 major haplotype blocks. Three valid SNPs at the GAD2 gene demonstrated no associations with alcoholism. Further permutation tests in the only 1 haplotype block or individual SNPs demonstrated no significant differences. Conclusions: This is the first report indicating a possible significant role of the GAD1 gene in the development of alcohol dependence and/or the course of alcohol withdrawal and outcome of alcoholism.

Lorenzo A; Auguet T; Vidal F; Broch M; Olona M; Gutierrez C et al. Polymorphisms of alcohol-metabolizing enzymes and the risk for alcoholism and alcoholic liver disease in Caucasian Spanish women. Drug and Alcohol Dependence 84(2): 195-200, 2006. (28 refs.)

Background: The relationship of polymorphisms of the genes that encode for alcohol-metabolizing enzymes and individual vulnerability to alcoholism and alcoholic liver disease (ALD) in women is unclear. We determined the genotypes of ADHI B, ADHI C, CYP2E1 (Dra-I and Pst-I) and ALDH2 in a group of Caucasian Spanish women. Methods: We performed a cross-sectional case-control study. The study group was made of 220 women. Of these, 85 were alcoholic (27 without liver disease and 58 with alcoholic liver disease) and 135 were non-alcoholic (42 healthy controls and 93 with liver disease unrelated to alcohol). Genotyping of alcohol-metabolizing enzymes was performed using PCR-RFLP methods. Results: The distribution of the allelic variants (alleles 1 and 2) in the whole subjects analyzed was: ADH1B 91.6% and 8.4%; ADH1C 58.4% and 41.6%; CYP2E1 Dra-I 15% and 85%; CYP2E1 Pst-I 96.8% and 3.2%; and ALDH2 100% and 0%, respectively. Carriage of genotypes containing the ADH1B*2 mutant allele significantly protected against alcoholism [odds-ratio (OR)=0.00; 95% confidence interval (95% CI): 0.00-0.94; p=0.02] but was associated with an increased risk for alcoholic liver disease among alcohol-dependent women [OR=0.43; 95% CI: 0.18-0.41; p=0.004]. Analysis of the remaining loci showed no significant associations. Conclusions: In Caucasian Spanish women the ADH1B*2 allele modulates the risk for alcohol dependence and for alcoholic liver disease. Given the small number of alcoholic women analyzed here, these data need further validation in larger cohorts.

Loza AJM; Iglesias MTR; Diaz IP; Castellanos SC; Andrade CG; Mora MEM et al. Association of alcohol-metabolizing genes with alcoholism in a Mexican Indian (Otomi) population. Alcohol 39(2): 73-79, 2006. (56 refs.)

Association studies provide a powerful approach to link DNA variants and genetic predisposition to complex diseases. In this study, we determined the genotype and allelic frequencies of genes encoding enzymes involved in alcohol metabolism in alcoholic and nonalcoholic subjects of related ethnicity. A total of 118 individuals of Otomi Mexican Indian ancestry were included. Fifty-nine were chronic alcoholics according to WHO criteria and alcohol dependents according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria. They were compared to 59 teetotalers or alcohol consumers of < 10 g per day. The restriction fragment length polymorphisms analyzed were ADH1B/MaeIII, ALDH2/MboII, CYP2E1/DraI, CYP2E1/RsaI, and CYP2E1/TaqI. Of the studied polymorphisms, a significant difference between alcoholic and nonalcoholic Otomies was observed only in the CYP2E1/TaqI. The common genotype in alcoholics was A1/A2 (54%), and in nonalcoholics the homozygous A2/A2 (63%) (odds ratio [OR]: 0.28; 95% confidence interval [CI]: 0.13-0.60; P = .002). The frequency of the mutant allele A1 was significantly higher in alcoholics than in nonalcoholics (41 vs. 21%; OR: 2.4; 95% CI: 1.3-4.3; P = .003). This documents the presence of a polymorphism of CYP2E1 that is overexpressed in alcoholic Otomies, in which the variant allele (A1 of CYP2E1/TaqI) is associated with increased susceptibility to alcoholism. The appreciation that this finding may be an additional factor contributing to the high frequency of liver cirrhosis in Otomies requires further investigation.

Lu RB; Ko HC; Lee JF; Lin WW; Huang SY; Wang TJ et al. No alcoholism-protection effects of ADH1B2 allele in antisocial alcoholics among Han Chinese in Taiwan. Alcoholism: Clinical and Experimental Research* 29(12): 2101-2107, 2005. (64 refs.)

Background: Thomasson et al., (1991) suggested that the genetic variation at ADH1B and ALDH2 influences the risk of alcoholism. The ADH1B*2 and ALDH2*2 alleles had been thought to be protective against alcoholism. Recent studies have suggested that either physiological tolerance of blood acetaldehyde, or innate insensitivity to it, or both may play a crucial role in keeping alcoholism from developing by protecting against adverse reactions. ALDH inactive form resulting from ALDH2*2, which slows the elimination of acetaldehyde and the more active isozymes produced by ADH1B*2, could generate higher acetaldehyde levels and thus deter heavy drinking (Thomasson et al., 1991). The genotype frequency of ADH1B*2/*2 and ALDH2*(1/*2 or 2/*2), which are regarded protective against drinking behavior, is about 70% and 50%, respectively, among the Han Chinese population in Taiwan (Chen et al., 1999a). Most previous studies, however, have failed to separate the effects of antisocial personality disorder from those of alcoholism because of their high comorbidity. To understand the relationship among alcoholism, antisocial personality disorder, and the protective effects of ADH and ALDH, it is necessary to recruit individuals with antisocial personality disorder but without alcoholism. This study was designed to stratify subjects by various ADH1B and ALDH2 genotypes for a more effective association study. The strata were: antisocial alcoholics, antisocial non-alcoholics, community alcoholics, and normal controls. Methods: We recruited 579 Han Chinese individuals in Taiwan, intending to examine the alcoholism-protection effects of different ADH1B and ALDH2 genotypes with or without antisocial personality disorder. Results: We found no difference of ADH1B*2 allele frequency between the subjects of antisocial alcoholism and subjects of antisocial non-alcoholism, but we found significant difference of ALDH2*2 allele between these two groups. Conclusions: We concluded that there is no alcoholism-protection effect of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan.

Ma Y; Meregalli M; Hodges S; Davies N; Bogdanos DP; Fargion S. Alcohol dehydrogenase: An autoantibody target in patients with alcoholic liver disease. International Journal of Immunopathology and Pharmacology 18(1): 173-182, 2005. (32 refs.)

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13%, P<0.005), HBV infection (2/8, 25%, P=0.03), non-alcohol related disease (9/29, 23%, P<0.0001) and in normal controls (3/22, 14%, P<0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76% vs 34/64, 53%, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P<0.05), immunoglobulin A (P<0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.

Martin CS; Balaban CD; McBurney DH. Tonic and phasic processes in the acute effects of alcohol. Experimental and Clinical Psychopharmacology 14(2): 209-218, 2006. (30 refs.)

This article presents a novel method for measuring the acute effects of alcohol. One hundred twenty nonproblem drinkers aged 21-28 participated in 3 alcohol administration sessions that produced peak blood alcohol concentrations (BACs) near .09 g%. Subjective intoxication ratings were taken at multiple points across rising and falling BACs. Mathematical modeling techniques decomposed intoxication ratings into a tonic component sensitive to BAC level and a phasic component sensitive to BAC rate of change. This model provided a good fit to observed data. Tonic and phasic gain parameters showed high repeatability across sessions. The average phasic gain parameter was about 4 times larger than the average tonic gain parameter, indicating that subjective intoxication is usually more affected by BAC change than by BAC level. The associations of drinking practices with tonic and phasic gain parameters varied by gender and family history of alcoholism. Tonic-phasic modeling allows individual and group differences in the acute effects of alcohol to be studied as time-dynamic processes.

Matsuda T; Yabushita H; Kanaly RA; Shibutani S; Yokoyama A. Increased DNA damage in ALDH2-deficient alcoholics. Chemical Research in Toxicology 19(10): 1374-1378, 2006. (27 refs.)

Drinking alcohol is a risk factor for cancers of the oral cavity, pharynx, larynx, and esophagus. Although many studies suggest that acetaldehyde, a major metabolite of orally ingested alcohol, plays a crucial role in cancer initiation, the link between the aldehyde dehydrogenase-2 (ALDH2) genotype and acetaldehyde-derived DNA damage has not yet been explored. We have developed a sensitive and quantitative method for detecting the acetaldehyde- derived DNA adducts, N-2-ethyl-2'-deoxyguanosine (N-2-Et-dG), alpha-S-and alpha-R-methyl-gamma-hydroxy-1, N-2-propano-2'-deoxyguanosine (alpha-S-Me-gamma-OH-PdG and alpha-R-Me-gamma-OH-PdG), and N-2-(2,6-dimethyl-1,3-dioxan-4-yl)-deoxyguanosine (N-2-Dio-dG), by using liquid chromatography electrospray tandem mass spectrometry (LC/ESI-MS/MS) and stable-isotope internal standards. We determined the DNA adducts in 44 blood DNA samples from Japanese alcoholic patients. The levels of three acetaldehyde-derived DNA adducts, N-2-Et-dG, alpha-S-Me-gamma-OH-PdG, and alpha-R-Me-gamma-OH-PdG, were significantly higher in alcoholics with the ALDH2* 1/2* 2 genotype compared to those with the ALDH2* 1/2* 1 genotype. N-2-Dio-dG was not detected in any of the DNA samples analyzed. These results provide molecular evidence that the ALDH2 genotype affects the genotoxic damage caused by acetaldehyde.

Matsuo K; Hiraki A; Hirose K; Ito H; Suzuki T; Wakai K et al. Impact of the alcohol-dehydrogenase (ADH) 1C and ADH1B polymorphisms on drinking behavior in nonalcoholic Japanese. Human Mutation 28(5): 506-510, 2007. (33 refs.)

A linkage disequilibrium (LD) between the alcohol-dehydrogenase 1B (ADH1B) and alcohol-dehydrogenase 1C (ADH1C) polymorphisms adds complexity to differentiating the significance of these two genetic polymorphisms on drinking behavior and alcoholism. We have recently shown the importance of the ADH1B polymorphism on habitual drinking in the Japanese population; however, the issue regarding the LD between the ADH1B and ADH1C polymorphisms remains to be clarified. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese individuals. Drinking behavior was examined with regard to haplotypes of the ADH1B and ADH1C polymorphisms. Strength of association was assessed by sex and alaehyde-dehydrogenase 2 (ALDH2) adjusted odds ratios (OR) and their 95% confidence intervals (CIs) for the haplotype of the ADH1B and ADH1C polymorphisms. The ORs for habitual drinking were significant for ADH1B*2(rapid), ADHIC*2(slow) (OR = 1.03; 95% CI: 1.01-1.05), ADHIB*1 (slow)-ADH1C*1 (rapid) (OR = 1.15; 95% CI: 1.14-1.16), and ADH1B*1 (slow)-ADH1C*2 (slow) (OR= 1.31; 95% CI: 1.29-1.32) compared with ADH1B*2 (rapid) ADH1C*1 (rapid). This trend was evident among mates. Similarly, a significantly increased risk of heavy drinking was observed for each haplotype compared with ADH1B*2 (rapid)-ADH1C*1 (rapid). In conclusion, this study showed a significant impact of the ADH1C polymorphism on habitual drinking, regardless of the ADH1B/ALDH2 polymorphisms.

Matsuo K; Wakai K; Hirose K; Ito H; Saito T; Tajima K. Alcohol dehydrogenase 2 His(47) Arg polymorphism influences drinking habit independently of aldehyde dehydrogenase 2 Glu(487) Lys polymorphism: Analysis of 2,299 Japanese subjects. Cancer Epidemiology, Biomarkers & Prevention 15(5): 1009-1013, 2006. (18 refs.)

Although the functional effect of alcohol dehydrogenase 2 (ADH2) HiS(47)Arg polymorphism has been elucidated, its effect on habitual drinking remains unknown. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese subjects (989 men and 1,310 women). Drinking status, ethanol consumption, and physical reaction to one glass of beer were examined with regard to ADH2 and aldehyde dehydrogenase 2 (ALDH2) polymorphism. Strength of associations were assessed by age-, sex-, smoking status-, and genotype-adjusted odds ratios and their 95% confidence intervals. ADH2 His/Arg and Arg/Arg genotypes showed higher risk for habitual drinking. Among men, ALDH2 genotype- and confounder-adjusted odds ratios (95% confidence intervals) were 1.30 (0.89-1.89) and 3.16 (1.03-9.70), and this trend was significant (P = 0.024). A similar trend was observed among women. The combination genotypes of two polymorphisms revealed the clear effect of the ADH2 Arg allele among those with ALDH2 Glu/Lys in both sexes (P-trend = 0.007 for men and 0.024 for women). Physical reactions, such as flushing and palpitation, were significantly less common in those with Arg/Arg compared with other ADH2 genotypes, and this was marked when combined with ALDH2 Glu/Lys. Heavy drinker status was also strongly associated with ADH2 Arg alleles. In conclusion, this study showed the strong effect of ADH2 HiS(47)Arg polymorphism on habitual drinking regardless of ALDH2 genotype.

Meier P; Seitz HK. Age, alcohol metabolism and liver disease. Current Opinion in Clinical Nutrition and Metabolic Care 11(1): 21-26, 2008. (43 refs.)

Purpose of review: Alcohol consumption among the elderly has increased. Alcohol metabolism changes with age and the elderly are more sensitive to the toxic effects; this increased consumption is therefore of great clinical relevance. Recent findings: Metabolism of ethanol changes with advancing age because activity of the enzymes involved, such as alcohol and acetalclehyde dehydrogenase and cytochrome P-4502E1, diminish with age. The water distribution volume also decreases with age. Both lead to increased blood concentrations of ethanol. Also, elderly people take more drugs, and ethanol and these drugs may interact; therefore, alcohol consumption can modify serum drug concentrations and their toxicity. Finally, elderly people may suffer more frequently from other types of liver disease, and alcohol may exacerbate these. Summary: Over recent decades alcohol consumption has increased among those who are older than 65 years. Alcohol is more toxic in the ageing organism because of changes in its metabolism, distribution and elimination, which lead to central nervous system effects at lower levels of intake; also, ageing organs such as brain and liver are more sensitive to the toxicity of alcohol. For these reasons, alcohol should be used in moderation, especially among those of older age.

Minegishi Y; Tsukino H; Muto M; Goto K; Gernma A; Tsugane S et al. Susceptibility to lung cancer and genetic polymorphisms in the alcohol metabolite-related enzymes alcohol dehydrogenase 3, aldehyde dehydrogenase 2, and cytochrome P450 2E1 in the Japanese population. Cancer 110(2): 353-362, 2007. (42 refs.)

BACKGROUND. it is believed that acetaldehyde plays an important role in alcohol-related carcinogenesis; although current epidemiologic studies have provided inconsistent findings on the association between alcohol consumption and the risk of lung cancer. METHODS. To clarify the hypothesis that genetic polymorphisms in alcohol-metabolizing enzymes may influence susceptibility to lung cancer, the authors conducted a hospital-based case-control study and examined genetic polymorphisms in the alcohol dehydrogenase 3, aldehyde dehydrogenase 2 (ALDH(2)), and cytochrome P450 2131 genes in 505 patients with histologically confirmed lung cancer and in a group of 256 noncancer controls who provided complete cigarette and alcohol consumption histories. Genotyping was conducted by polymerase chain reaction-restriction fragment-length polymorphism assay. RESULTS. A significant association was noted between alcohol consumption and lung cancer risk. Thus, using the median value for the controls as the cut-off point, the odds ratios (OR) for light and heavy drinkers were 1.76 and 1.95, respectively (P for trend =.012), compared with nondrinkers. In addition, there was a significant trend toward increased risk of lung cancer in drinkers with ALDH2 variant alleles (P for trend <.0001). The adjusted OR for heavy drinkers was 6.15 compared with nondrinkers. Regarding associations between histologic type and genotypes, the ALDH(2) variant allele was significantly less common in patients who had adenocarcinoma compared with controls. CONCLUSIONS. The current observations suggested a positive association between alcohol consumption and the risk of lung cancer: Drinking may increase the risk, especially among individuals who have the variant ALDH(2) alleles.

Moore S; Montane-Jaime LK; Carr LG; Ehlers CL. Variations in alcohol-metabolizing enzymes in people of East Indian and African descent from Trinidad and Tobago. Alcohol Research & Health 30(1): 28-30, 2007. (12 refs.)

The population of Trinidad and Tobago is composed mainly of people of East Indian (indo-Trinidadians) and African (Afro-Trinidadians) ancestry. Differences in alcoholism rates exist between these two ethnic groups, and researchers have investigated whether these differences can be explained in part by variations in the genes encoding the alcohol-metabolizing enzymes alcohol dehydrogenase (ADH) III and IC, and aldehyde dehydrogenase (ALDH) I and 2. Studies have demonstrated that a certain variant of the gene encoding ADH1B (ADH1B*3) is associated with a reduced risk of alcoholism in Afro- Trinidadians, as is a variant of the gene encoding ADH1C (i.e., ADH1C*1) in Indo-Trinidadians. An ALDH2 variant shown to have protective effects primarily in East Asians was not found in either Trinidadian ethnic group. However, a variant in the gene encoding cytosolic ALDH1A (i.e. ALDH1A1*1/*2) was found to be associated with an increase in alcohol dependence in Indo-Trinidadians.

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Myers AL; Williams HE; Kraner JC; Callery PS. Identification of anhydroecgonine ethyl ester in the urine of a drug overdose victim. Journal of Forensic Sciences 50(6): 1481-1485, 2005. (36 refs.)

Toxicological evaluation of postmortem urine collected from a 41-year-old deceased white male detected anhydroecgonine ethyl ester (ethyl ecgonidine, AEEE), a transesterification product of smoked cocaine co-abused with ethanol. A solid phase extraction (SPE) method was used to extract cocaine, AEEE, and related metabolites from urine. SPE on a 1 mL urine sample from the decedent followed by GC-MS detected AEEE. Other metabolites identified by GC-MS included cocaine, cocaethylene, and anhydroecgonine methyl ester (AEME). To determine whether some or all of the AEEE was artifactually produced in the heated GC injector port, an alternative LC-MS method was developed. LC/MS following of AEEE detected in the urine was compared to SPE found at least 50 ng/mL of AEEE in the extract. The mass fragmentation (MS/MS and MS3) spectra of authentic, synthesized compound. AEEE is a potential additional forensic market for the co-abuse of smoked cocaine and ethanol.

Parlesak MHU; Billinger C; Schafer HD; Wehner C; Bode JC et al. First-pass metabolism of ethanol in human beings: Effect of intravenous infusion of fructose. Alcohol 34(2/3): 121-125, 2005. (23 refs.)

I Intravenous infusion of fructose has been shown to enhance reduced form of nicotinamide adenine dinucleotide reoxidation and, thereby, to enhance the metabolism of ethanol. In the current study, the effect of fructose infusion on first-pass metabolism of ethanol was studied in human volunteers. A significantly higher first-pass metabolism of ethanol was obtained after administration of fructose in comparison with findings for control experiments with an equimolar dose of glucose. Because fructose is metabolized predominantly in the liver and can be presumed to have virtually no effects in the stomach, results of the current study support the assumption that only a negligible part of first-pass metabolism of ethanol occurs in the stomach.

Patrick KS; Straughn AB; Minhinnett RR; Yeatts SD; Herrin AE; DeVane CL et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clinical Pharmacology & Therapeutics 81(3): 346-353, 2007. (31 refs.)

This study explores the hypotheses that: (1) ethanol will interact with di-Methylphenidate (MPH) to enantioselectively elevate plasma d-MPH, and primarily yield l-ethylphenidate as a transesterification metabolite; (2) women will exhibit lower relative bioavailability of MPH than men; and (3) sex-dependent differences in subjective effects will exist. dI-MPH HCl (0.3 mg/kg) was administered orally 30 min before ethanol, 30 min after ethanol (0.6 gm/kg), or without ethanol, in a randomized, normal subject three-way crossover study of 10 men and 10 women. Pharmacokinetic parameters were compared. Subjective effects were recorded using visual analog scales. One subject was a novel poor MPH metabolizer whose data were analyzed separately. Ethanol after or before MPH significantly (P < 0.0001) elevated the geometric mean for the maximum d-MPH plasma concentration (C-max (+/- SD)) from 15.3 (3.37) ng/ml to 21.5 (6.81) and 21.4 (4.86), respectively, and raised the corresponding geometric mean for the area under the concentration-time curve values from 82.9 (21.7) ng ml/h to 105.2 (23.5) and 102.9 (19.2). I-MPH was present in plasma only at 1-3% of the concentration of d-MPH, except in the poor metabolizer where I-MPH exceeded that of d-MPH. The metabolite l-ethylphenidate frequently exceeded 1 ng/ml in plasma, whereas d-ethylphenidate was detected only in low pg/ml concentrations. Women reported a significantly greater stimulant effect than men when questioned "Do you feel any drug effect?" (P < 0.05), in spite of lower mean plasma d-MPH area under the response-time curves in women. Ethanol elevates plasma d-MPH C-max and area under the concentration-time curve by approximately 40% and 25%, respectively. If the poor metabolizer of MPH proves to be a distinct phenotype, determining the genetic mechanism may be of value for individualizing drug therapy. The more pronounced stimulant effects experienced by women have sex-based abuse liability implications.

Pavlic M; Libiseller K; Grubwieser P; Ulmer H; Sauper T; Rabl W. Another 'soberade' on the market: does Outox keep its promise? Wiener Klinische Wochenschrift 119(3-4): 104-111, 2007. (33 refs.)

Objective: Several products are being widely promoted for reduction of the concentration of alcohol in the human body. One of these preparations, the fructose soft drink Outox, claims to noticeably increase the alcohol elimination rate (beta 60). Theories to explain this 'fructose effect' are based on the assumption that NAD+, the coenzyme for alcohol dehydrogenase, is regenerated faster in the presence of fructose. Method: A randomized double-blind, placebo-controlled cross-over study was performed with 30 volunteers in two drinking sessions each. Under strictly identical conditions, the same amount of alcohol was consumed, followed by the consumption of either 250 ml Outox or 250 ml placebo. Periodical measurements of blood (BAC), breath (BrAC) and urine alcohol concentration (UAC) were performed. Results: Analyses revealed a significant difference (P < 0.0001) between the mean alcohol levels of the Outox and the placebo drinking sessions. The overall mean BAC difference was 0.077 g/l (BAC 0.748 g/l without vs 0.671 g/l with Outox), equivalent to 10.3%. The mean BrAC difference was 0.045 mg/l (BrAC 0.314 mg/l without vs 0.269 mg/l with Outox), equivalent to 14.3%. Differences were lower for women than for men. A significant difference between the alcohol elimination rates (beta 60) was not found. Conclusions: The results show that the soft drink Outox may decrease the alcohol concentration by about 10%. However, BAC and BrAC differences are rather a consequence of slower gastric absorption of alcohol, because Outox does not increase the alcohol elimination rate. Our study demonstrates that the claim of Outox or other fructose drinks to work as a 'soberade' cannot be proven from a scientific point of view. It should be the task of physicians to warn potential consumers, especially in connection with drinking and driving.

Pedersen-Bjergaard U; Reubsaet JLE; Nielsen SL; Pedersen-Bjergaard S; Perrild H; Pramming S et al. Psychoactive drugs, alcohol, and severe hypoglycemia in insulin-treated diabetes: Analysis of 141 cases. American Journal of Medicine 118(3): 307-310, 2005. (27 refs.)

By systematically screening for alcohol and drugs, we identified a psychoactive substance in one third of blood samples from diabetic patients with severe hypoglycemia. Episodes of severe hypoglycemia are often complicated by a temporary memory deficit, and exposure to illicit drugs and alcohol is generally underreported. Therefore, reliance on a patient's own testimony has limited value, and independent biochemical verification is important. In a previous series of severe hypoglycemia, alcohol intake has been reported in 4% to 19% of episodes, similar to the frequency of positive blood alcohol screens in our study (17%). We found that psychoactive drugs were present in blood screens with a similar frequency (18%) as alcohol, divided evenly between pharmaceutical and illicit agents. Perhaps drug-induced impairment of cognitive function lessens the awareness of the need for self-treatment of hypoglycemia. Some drugs affect carbohydrate metabolism or glucose counterregulation. Alternatively, use of drugs and increased risk of severe hypoglycemia may share a common cause, such as less meticulous self-care. Finally, chronic use or abuse of drugs may lead to behavioral changes, such as irregular eating habits, which may increase the risk of severe hypoglycemia. People with diabetes are educated to understand the relation between alcohol consumption and the risk of severe hypoglycemia and to avoid excessive alcohol intake. It is possible that the younger diabetic patients in this study have instead been attracted to use psychoactive drugs that were not known to cause hypoglycemia.

Pepino MY; Steinmeyer AL; Mennella JA. Lactational state modifies alcohol pharmacokinetics in women. Alcoholism: Clinical and Experimental Research 31(6): 909-918, 2007. (62 refs.)

Background: Given the physiological adaptations of the digestive system during lactation, the present study tested the hypothesis that lactation alters alcohol pharmacokinetics. Methods: Lactating women who were exclusively breastfeeding a 2- to 5-month-old infant and 2 control groups of nonlactating women were studied. The first control group consisted of women who were exclusively formula-feeding similarly aged infants, whereas the other consisted of women who had never given birth. A within-subjects design study was conducted such that women drank a 0.4 g/kg dose of alcohol following a 12-hour overnight fast during one test session (fasted condition) or 60 minutes after consuming a standard breakfast during the other (fed condition). Blood alcohol concentration (BAC) levels and mood states were obtained at fixed intervals before and after alcohol consumption. Results: Under both conditions, the resultant BAC levels at each time point were significantly lower and the area under the blood alcohol time curve were significantly smaller in lactating women when compared with the 2 groups of nonlactating women. That such changes were due to lactation per se and not due to recent parturient events was suggested by the finding that alcohol pharmacokinetics of nonlactating mothers, who were tested at a similar time postpartum, were no different from women who had never given birth. Despite lower BAC levels in lactating mothers, there were no significant differences among the 3 groups of women in the stimulant effects of alcohol. However, lactating women did differ in the sedative effects of alcohol when compared with nulliparous but not formula-feeding mothers. That is, both groups of parous women felt sedated for shorter periods of time when compared with nulliparous women. Conclusions: The systemic availability of alcohol was diminished during lactation. However, the reduced availability of alcohol in lactating women did not result in corresponding changes in the subjective effects of alcohol.

Preedy VR; Watson R. Comprehensive Handbook of Alcohol Related Pathology. San Diego: Elsevier Science, 2005. (Chapter refs.)

This is a three volume reference series, with over 120 chapters, dealing with all aspects of alcohol related pathology. Part I, with 20 chapters, deals with general aspects of alcohol toxicity, consumption and disease. This includes consideration of alcohol metabolism, genetic aspects of metabolism, predictors of consumption, breath and blood alcohol, effects of food and body composition on BAC, effects of alcohol on water and sodium homeostasis, energy from alcohol, the Mediterranean diet and contribution of alcohol, alcohol and injury deaths, alcohol poisoning, and alcohol use by special populations and settings. Part II, with 54 chapters, covers damage/disease, general aspects of pathology, organ damage, cells, pathways, interactions, and processes, organized by organ system. Among the topics addressed are gastrointestinal tract, pancreatitis, hepatitis, effects on vascular function, molecular mechanisms in fetal alcohol syndrome, hormonal responses, DNA damage from alcohol abuse, alcohol abuse and eating disorders, role of acetaldehyde, and tryptophan metabolism and alcoholism. Part III, with 21 chapters, deals with selective methods used in alcohol research. Some of the topics addressed include screening in primary care, psychometric assessment, use of DSN-IN, various screening instruments, methods for determining BAC, urinary markers of alcohol consumption, measuring generic variations in ADH, assays for alcohol and alcohol dehydrogenase, selectively bred alcohol-preferring rats, animal models of alcohol-induced liver disorders, acute alcohol dosing regimens, animal models of fetal damage, cDNA arrays in alcohol-related pathology, measuring facial dysmorphology in FAS, and nuclear magnetic resonance.

Quertemont E; Grant KA; Correa M; Arizzi MN; Salamone JD; Tambour S et al. The role of acetaldehyde in the central effects of ethanol. Alcoholism: Clinical and Experimental Research 29(2): 221-234, 2005. (80 refs.)

This article represents the proceedings of a symposium at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, Canada. The symposium was organized by Etienne Quertemont and chaired by Kathleen A. Grant. The presentations were (1) Behavioral stimulant effects of intracranial injections of ethanol and acetaldehyde in rats, by Merc Correa, Maria N. Arizzi and John D. Salamone; (2) Behavioral characterization of acetaldehyde in mice, by Etienne Quertemont and Sophie Tambour; (3) Role of brain catalase and central formed acetaldehyde in ethanol's behavioral effects, by Carlos M.G. Aragon; (4) Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats, by William J. McBride, Zachary A. Rodd, Avram Goldstein, Alejandro Zaffaroni and Ting-Kai Li; and (5) Acetaldehyde increases dopaminergic transmission in the limbic system, by Milena Pisano and Marco Diana.

Salme RO; Laposata M; Rajendram R; Cluette-Brown JE; Preedy VR. The total body mass of fatty acid ethyl esters in skeletal muscles following ethanol exposure greatly exceeds that found in the liver and the heart. Alcohol and Alcoholism 41(6): 598+, 2006. (38 refs.)

Aims: Skeletal muscle appears to be susceptible to chronic and acute excess alcohol intake, giving rise to alcoholic myopathy, a common disease among alcoholics. Fatty acid ethyl esters (FAEE), non-oxidative metabolites of ethanol, have been shown to be toxic to cells in vitro and in vivo. We hypothesized that accumulation of FAEE in skeletal muscle could contribute to the development of alcoholic myopathy. Methods: Male wistar rats were treated either with 75 mmol ethanol/kg body weight or saline, in the fed state or starved for 1 or 2 days before administration. Rats were thus divided into the following groups: fed-saline (n = 8); fed-ethanol (n = 8); starved 1 day, saline (n = 8); starved 1 day, ethanol (n = 9); starved 2 days, saline (n = 7); and starved 2 days, ethanol (n = 8). At the end of the incubation, skeletal muscles (abdominal and gastrocnemius), liver, and heart were isolated and processed for FAEE isolation and analysis by gas chromatography-mass spectrometry (GC-MS). Results: Total mass of FAEE in the muscles was much greater than that found in the liver and the heart. In general, the animals that were fasted for 1 day and received ethanol had the highest FAEE levels among the three groups of animals. The major ethyl ester species in all cases were ethyl 16:0, ethyl 18:0, ethyl 18:1 n-9, and ethyl 18:2 n-6. Ethyl 20:4 n-6 and ethyl 22:6 n-3 were also present, except in the fasted 1-day group, where ethyl 22:6 disappeared, though it reappeared in the fasted 2-day group. Conclusion: These findings demonstrate that skeletal muscles contain high levels of FAEE that are synthesized in the body after ethanol exposure. The concentration of FAEE in skeletal muscle in this study was very similar to FAEE concentration in the liver. This differs from previous studies suggesting a low concentration of skeletal muscle FAEE with ethanol exposure.

Scott DM; Taylor RE. Health-related effects of genetic variations of alcohol-metabolizing enzymes in African Americans. Alcohol Research & Health 30(1): 18-21, 2007. (27 refs.)

Alcohol metabolism involves two key enzymes-alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are several types of ADH and ALDH, each of which may exist in several variants (i.e., isoforms) that differ in their ability to break down alcohol and its toxic metabolite acetaldehyde. The isoforms are encoded by different gene variants (i.e., alleles) whose distribution among ethnic groups differs. One variant of ADH Is ADH1B, which is encoded by several alleles. An allele called ADH1B*3 is unique to people of African descent and certain Native American tribes. This allele is associated with more rapid breakdown of alcohol, leading to a transient accumulation of acetaldehyde. African Americans carrying this allele are less likely to have a family history of alcoholism and experience a less rewarding subjective response to alcohol. Moreover, children of mothers with this allele are less vulnerable to alcohol-related birth defects. The enzyme ALDH1 also is encoded by several alleles. Two of these alleles that are found in African Americans - ALDH1 A1 *2 and ALDH1 A1 *3 - may be associated with a reduced risk of alcoholism.

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Seitz HK; Becker P. Alcohol metabolism and cancer risk. Alcohol Research & Health 30(1): 38+, 2007. (31 refs.)

Chronic alcohol consumption increases the risk for cancer of the organs and tissues of the respiratory tract and the upper digestive tract (i.e., upper aerodigestive tract), liver, colon, rectum, and breast. Various factors may contribute to the development (i.e., pathogenesis) of alcohol-associated cancer, including the actions of acetaldehyde, the first and most toxic metabolite of alcohol metabolism. The main enzymes involved in alcohol and acetaldehyde metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are encoded by multiple genes. Because some of these genes exist in several variants (i.e., are polymorphic), and the enzymes encoded by certain variants may result in elevated acetaldehyde levels, the presence of these variants may predispose to certain cancers. Several mechanisms may contribute to alcohol-related cancer development. Acetaldehyde itself is a cancer-causing substance in experimental animals and reacts with DNA to form cancer-promoting compounds. In addition, highly reactive, oxygen-containing molecules that are generated during certain pathways of alcohol metabolism can damage the DNA, thus also inducing tumor development. Together with other factors related to chronic alcohol consumption, these metabolism-related factors may increase tumor risk in chronic heavy drinkers.

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Simic M; Tasic M. The relationship between alcohol elimination rate and increasing blood alcohol concentration. Calculated from two consecutive blood specimens. Forensic Science International 172(1): 28-32, 2007. (26 refs.)

In the period 1991-2005, a blood-alcohol concentration (BAC) analysis was carried out at the Institute of forensic medicine in Novi Sad including 2023 two consecutive blood specimens using the Headspace Gas Chromatography method. Cases with no alcohol concentration values, as well as cases where blood samples were taken within 1 h after the criminal act, were not taken into consideration. Following this rule, 1198 cases were considered in this study and all samples were grouped in 29 ranges of BAC(1) of Delta(BAC) = 0.1 g/kg, starting from 0.1-0.19 g/kg to 2.9-2.99 g/kg of absolute alcohol. Gathered results and elimination curve differ from the zero-order model of elimination proposed by Widmark and point to an elimination process similar to a well-known Michaelis-Menten elimination kinetics model and its variants. Results reported in this study show dependence of alcohol elimination rate (beta(60)-slope) and BAC value. The analysis of beta(60)-slope versus BAC shows that a correlation between beta(60)(y) and BAC (x) has a logarithmic trend line. The value of alcohol elimination rate shows a slight increment with increase of BAC alcohol, with the mean value of beta(60) = 0.221 +/- 0.075 g/kg. Differences in values of beta(60) among consecutive intervals of Delta(BAC) = 0.1 g/kg are not significant (p > 0.05). When obtained samples were grouped into ranges of 0.5 g/kg each in these intervals beta(60) had the following values by range: 0.1-0.49 g/kg = 0.139 g/kg +/- 0.035; 0.5-0.99 g/kg = 0.184 g/kg +/- 0.043; 1-1.49 g/kg = 0.213 g/kg +/- 0.052; 1.5-1.99 g/kg = 0.239 g/kg +/- 0.058; 2-2.49 g/kg = 0.265 g/kg +/- 0.073; 2.5-2.99 g/kg = 0306 g/kg +/- 0.096. Differences in values of beta slope among consecutive intervals of Delta(BAC) = 0.5 g/kg are significant (p < 0.01). The elimination curve in the BAC interval 0.5-2.5 g/kg has a linear trend, while beta-slope (y)/BAC (x) correlation is given as beta(60) = 0.15 g/kg + (0.05 g/kg x BAC). Retrograde calculation of the blood alcohol concentration in tempore criminis (BAC(tc)) based on the determined alcohol concentration in the blood specimen (BAC(t)) shows a statistically significant difference between BAC(tc) calculated using a standard zero-order model versus corrected methodology. The higher the BAC(t) and the longer the calculation time, the greater and statistically more significant (p < 0.01) is the difference between the calculated values of BAC(tc).

Terry MB; Knight JA; Zablotska L; Wang Q; John EM; Andrulis IL et al. Alcohol metabolism, alcohol intake, and breast cancer risk: A sister-set analysis using the Breast Cancer Family Registry. Breast Cancer Research and Treatment 106(2): 281-288, 2007. (37 refs.)

Moderate alcohol intake has been consistently associated with a modest (30-50%) increase in breast cancer risk, but it remains unclear if certain individuals have higher susceptibility to the harmful effects of alcohol intake. Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase (ADH), the enzyme that catalyzes the oxidation of approximately 80% of ethanol to acetaldehyde, a known carcinogen. Using data from the Breast Cancer Family Registry (n = 811 sister sets), we examined whether sisters with breast cancer differ with respect to alcohol consumption and alcohol metabolism (measured by polymorphisms in ADH1B and ADH1C) compared to their sisters without breast cancer. Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were associated with breast cancer risk. However, only 19% and 42% of sisters were discordant by ADH1B and ADH1C, respectively, and even fewer were discordant by both genotype and alcohol intake, making it difficult to detect differences if they existed.

Umulis DM; Gurmen NM; Singh P; Fogler HS. A physiologically based model for ethanol and acetaldehyde metabolism in human beings. Alcohol 35(1): 3-12, 2005. (24 refs.)

Pharmacokinetic models for ethanol metabolism have contributed to the understanding of ethanol clearance in human beings. However, these models fail to account for ethanol's toxic metabolite, acetaldehyde. Acetaldehyde accumulation leads to signs and symptoms, such as cardiac arrhythmias, nausea, anxiety, and facial flushing. Nevertheless, it is difficult to determine the levels of acetaldehyde in the blood or other tissues because of artifactual formation and other technical issues. Therefore, we have constructed a promising physiologically based pharmacokinetic (PBPK) model, which is an excellent match for existing ethanol and acetaldehyde concentration-time data. The model consists of five compartments that exchange material: stomach, gastrointestinal tract, liver, central fluid, and muscle. All compartments except the liver are modeled as stirred reactors. The liver is modeled as a tubular flow reactor. We derived average enzymatic rate laws for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), determined kinetic parameters from the literature, and found best-fit parameters by minimizing the squared error between our profiles and the experimental data. The model's transient output correlates strongly with the experimentally observed results for healthy individuals and for those with reduced ALDH activity caused by a genetic deficiency of the primary acetaldehyde-metabolizing enzyme ALDH2. Furthermore, the model shows that the reverse reaction of acetaldehyde back into ethanol is essential and keeps acetaldehyde levels approximately 10-fold lower than if the reaction were irreversible.

Wakabayashi I; Masuda H. Influence of drinking alcohol on atherosclerotic risk in alcohol flushers and non-flushers of oriental patients with type 2 diabetes mellitus. Alcohol and Alcoholism 41(6): 672-677, 2006. (36 refs.)

Aims: Facial flushing caused by alcohol drinking is a typical symptom of high sensitivity to alcohol in orientals. We investigated whether drinking alcohol influences atherosclerotic risk factors in alcohol flushers and non-flushers in patients with diabetes mellitus. Methods: A cross-sectional study was performed using 225 subjects with type 2 diabetes. Sensitivity to alcohol was surveyed by a questionnaire on facial flushing. Subjects were divided into three groups by average amount of alcohol drinking (non-drinkers; light drinkers: < 140 g/week; heavy drinkers: 140 g/week or more). Results: Systolic blood pressure and blood HDL cholesterol were significantly higher in heavy drinkers than in non-drinkers. There were no significant differences in body mass index, blood pressure, blood total cholesterol, HDL cholesterol, uric acid, fibrinogen and sialic acid levels in flushers and non-flushers. In alcohol flushers, diastolic blood pressure and HDL cholesterol in heavy drinkers were significantly higher than those in non-drinkers, and systolic blood pressure was significantly higher in heavy drinkers than in non-drinkers and light drinkers. On the other hand, blood pressure and HDL cholesterol in non-flushers were not significantly different among non-, light and heavy drinkers. Serum total cholesterol was not significantly different among the three drinking groups both in flushers and non-flushers. Conclusions: Blood pressure and HDL cholesterol are more prone to be affected by drinking in flushers than in non-flushers, suggesting that alcohol sensitivity evaluated by flushing response due to drinking alcohol should be taken into account when the effects of alcohol drinking on atherosclerotic risk factors are considered in oriental patients with type 2 diabetes mellitus.

Wall TL. Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action. Therapeutic Drug Monitoring 27(6): 700-703, 2005. (72 refs.)

Two alcohol dehydrogenase genes (ADH1B and ADH1C on chromosome 4) and one aldehyde dehydrogenase gene (ALDH2 on chromosome 12) exhibit functional polymorpbisms that are associated with lower rates of alcohol dependence. The ALDH2*2 allele, found almost exclusively in Asian populations, has the strongest relationship. The ADH1B*2, ADH1B*3, and ADH1C*1 alleles, found in varying prevalence in different ethnic groups, have also been associated with lower rates of alcohol dependence. Studies of the ADH1B and ADH1C haplotypes, however, have shown that ADH1C*1 is in linkage disequilibrium with ADH1B*2, and the ADH1C*1 allele does not appear to have significant unique associations with alcohol dependence. The hypothesized mechanism underlying the associations of the ADH1B and ALDH2 polymorphisms with alcohol dependence is that the isoenzymes encoded by these alleles lead to an accumulation of acetaldehyde during alcohol metabolism. Based on their kinetic properties, ALDH2*2 theoretically should lead to a slower removal of acetaldehyde than ALDH2*1, whereas ADH1B*2 and ADH1B*3 should lead to a more rapid production of acetaldehyde than ADH1B*L It is further hypothesized that elevations in acetaldehyde cause more intense reactions to alcohol and lead to lower levels of alcohol intake. Data are consistent with the hypothesis that elevations in acetaldehyde, increased sensitivity to alcohol, and lower levels of drinking reflect the mechanism by which the ALDH2*2 allele reduces risk for alcohol dependence. There is also some evidence supporting this mechanism for the ADH1B*2 and ADH1B*3 alleles, but the results are less consistent. These findings highlight the value of trying to elucidate the mechanism by which genes ultimately give rise to differences in alcohol dependence through the examination of mediating behaviors.

Wang DH; Ritchie JM; Smith EM; Zhang ZG; Turek LP; Haugen TH. Alcohol dehydrogenase 3 and risk of squamous cell carcinomas of the head and neck. Cancer Epidemiology, Biomarkers & Prevention 14(3): 626-632, 2005. (44 refs.)

In order to examine the association between alcohol dehydrogenase 3 (ADH3) genotypes and risk of head and neck squamous cell carcinomas (HNSCC), we conducted a hospital based case-control study including 348 cases and 330 controls. DNA isolated from exfoliated cells from the oral cavity were genotyped for ADH3 polymorphisms using PCR followed by SspI digestion. Odds ratios (OR) and hazards ratios (HR) were done by unconditional logistic regression and Cox regression. Relative to ADH3(2-2) carriers, ADH3(1-1) [OR, 0.7; 95% confidence interval (0), 0.4-1.1] and ADH3(1-2) (OR, 0.8; 95% Cl, 0.5-1.2) had a nonsignificant reduced risk of HNSCC. ADH(1-2) smokers of >30 pack-years were at decreased risk of oral cavity squamous cell carcinomas compared with ADH3(2-2) (OR,, 0.3, 0.1-0.9), whereas ADH3(1-1) smokers were not. After adjustment, those with ADH3(1-2) had significantly worse overall survival compared with ADH3(1-1) (HR, 0.3, 0.2-0.6) or ADH3(2-2) (HR, 0.4, 0.2-0.9) and increased recurrence (ADH3(1-1), 0.2, 0.1-0.6; ADH3(2-2), 0.6, 0.2-1.3). Our data did not show that ADH3 genotypes had a significantly independent effect on the risk of HNSCC, nor did they modify the risks increased by alcohol or tobacco consumption and high-risk human papillomavirus infection. However, participants with ADH3(1-2) genotype were associated with poorer survival compared with those who had the other two ADH3 genotypes and a higher rate of recurrence than participants with ADH3(1-1) genotype.

Whitfield JB. Alcohol and gene interactions. Clinical and Laboratory Medicine 43(5): 480-487, 2005. (53 refs.)

Alcohol use produces both desirable and undesirable effects, ranging from short-term euphoria and reduction in cardiovascular risk, to violence, accidents, dependence and liver disease. Outcomes are affected by the amount of alcohol used (which is itself affected by genetic variation) and also by the drinker's genes. Genetic effects have been most clearly demonstrated for alcohol dependence, and several of the genes for which variation leads to increased dependence risk have been identified. These include genes for enzymes involved in alcohol metabolism (alcohol dehydrogenase and aldehyde dehydrogenase), and genes for receptors affected by alcohol (particularly gamma-aminobutyric acid receptors). Many other gene/ dependence associations have been reported but not fully substantiated. Genetic effects on phenotypes other than alcohol dependence are less well understood, and need to be clarified before a full picture of gene-alcohol interactions can be achieved.

Wurst FM; Dresen S; Allen JP; Wiesbeck G; Graf M; Weinmann W. Ethyl sulphate: A direct ethanol metabolite reflecting recent alcohol consumption. Addiction 101(2): 204-211, 2006. (37 refs.)

Background: Ethyl sulphate (EtS), a direct ethanol metabolite, appears to offer potential as a biomarker for recent alcohol consumption. Although its window of assessment is similar to that of ethyl glucuronide (EtG), there are differences between the two markers in their pathways for formation and degradation. Aims: (a) To assess the excretion of EtS compared to EtG and ethanol in drinking experiments with healthy volunteers, and (b) to elucidate the possibility of using the two metabolites for monitoring abstinence in substance use disorder patients during rehabilitation treatment. Design, setting, participants (a) Nine drinking experiments were performed by six healthy volunteers (two females, four males), with a mean age of 34.1 years (20-62), average oral intake of 0.2 g/kg ethanol (0.1-0.61), and having 74 spot urine samples. (b) Thirty-six substance abuse patients (mean age 41.9 years, 20-59; 22 males, 14 females) in a rehabilitation programme after withdrawal, producing 98 urine samples. Ethyl glucuronide and ethyl sulphate were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS) using d(5)-EtG and d(5)-EtS, respectively, as an internal standard. Findings: (a) Volunteers: EtG and EtS were detectable for up to 36 hours and reached the limits of determination in urine at 20.6 hours and 21.2 hours (median), respectively, after ethanol intake. EtG-100 (standardized to a creatinine of 100 mg/dl) reached its maximum level at 2.8 hours and EtS-100 at 2.1 hours (median) after the beginning of the experiment. Of the ethanol ingested, 0.022% was excreted as EtS in one volunteer. Eight samples were positive for EtS only and six for EtG only. Spearman's rank correlation coefficients of 0.84 (P < 0.0001) between EtG and EtS and 0.87 (P < 0.0001) between EtG-100 and EtS-100 were found. (b) Patients: of the 98 urine samples evaluated, 27 were positive for EtS and of these only 20 were also positive for EtG. Spearman's rank correlation coefficients of 0.84 (P < 0.0001) between EtG and EtS and 0.82 (P < 0.0001) between EtG-100 and EtS-100 were found. Conclusions: The data from patients and volunteers suggest that the direct ethanol metabolite ethyl sulphate has the potential to serve as a biomarker of recent ethanol intake. Because EtG and EtS are formed via different pathways they might be used conjointly, thereby increasing sensitivity.

Wurst FM; Tabakoff B; Alling C; Aradottir S; Wiesbeck GA; Muller-Spahn F et al. World Health Organization/International Society for Biomedical Research on Alcoholism study on state and trait markers of alcohol use and dependence: Back to the future. Alcoholism: Clinical and Experimental Research 29(7): 1268-1275, 2005. (50 refs.)

This article summarizes content proceedings of a symposium held at the 2004 International Society for Biomedical Research on Alcoholism Congress in Mannheim, Germany. The chairs were Boris Tabakoff and Friedrich M. Wurst. The presentations were (1) Genetic associations with alcoholism and affective disorders, by Paula Hoffman; (2) Proteomic analysis of blood constituents in alcoholism, by Boris Tabakoff; (3) Contrasts between the responses of GGT and CDT to high alcohol intake, and a test of their combined use, by John Whitfield; (4) Direct ethanol metabolites such as ethyl glucuronide, fatty acid ethyl esters, phosphatidylethanol and ethyl sulfate: a new line of sensitive and specific biomarkers, by Friedrich Martin Wurst; and (5) Genetic studies of alcoholism subtypes in a Han Taiwanese population, by Ru-Band Lu.

Xu BJ; Zheng YN; Sung CK. Natural medicines for alcoholism treatment: A review. Drug and Alcohol Review 24(6): 525-536, 2005. (113 refs.)

Alcoholism is a serious problem throughout the world. The development of alcoholism remedies have medical, social and economical significance. In view of the pitfalls of psychological dependence and adverse behavioural effects of synthetic drugs, the development of low toxicity and high efficiency medicines derived from natural products exhibits expansive market prospects. Based on these considerations, we summarize briefly folk application of traditional hangover remedies and clinical application of herbal complex and patent medicines for alcoholism treatment. We have reviewed the effects of natural medicines on intake, absorption and metabolism of alcohol, as well as the protective effects on alcohol-induced acute and chronic tissue injury.

Yang SJ; Wang HY; Li XQ; Du HZ; Zheng CL; Chen HG et al. Genetic polymorphisms of ADH2 and ALDH2 association with asophageal cancer risk in southwest China. World Journal of Gastroenterology 13(43): 5760-5764, 2007. (27 refs.)

AIM: To evaluate the impact of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) polymorphisms on esophageal cancer risk. METHODS: One hundred and ninety-one esophageal cancer patients and 198 healthy controls from Yanting County were enrolled in this study. ADH2 and ALDH2 genotypes were examined by polymerase-chain-reaction with the confronting-two-pair-primer (PCR-CTPP) method. Unconditional logistic regression was used to calculate the odds ratios (OR) and 95% confidence interval (95% CI). RESULTS: Both ADH2*1 allele and ALDH2*1/*2 allele showed an increased risk of developing esophageal cancer. The adjusted OR (95% CI) for ADH2*1 allele compared with ADH2*2/*2 was 1.65 (95% CI = 1.02-2.68) and 1.67 (95% CI = 1.02-2.72) for ALDH2*1/*2 compared with ALDH2*1/*1. A significant interaction between ALDH2 and drinking was detected regarding esophageal cancer risk, the OR was 1.83 (95% CI = 1.13-2.95). Furthermore, when compared with ADH2*2/*2 and ALDH2*1/*1 carriers, ADH2*1 and ALDH2*2 carriers showed an elevated risk of developing esophageal cancer among non-alcohol drinkers (OR = 2.46, 95% CI = 0.98-6.14), and a significantly elevated risk of developing esophageal cancer among alcohol drinkers among alcohol drinkers (OR = 9.86, 95% CI 3.10-31.38). CONCLUSION: ADH2 and ALDH2 genotypes are associated with esophageal cancer risk. ADH2*1 allele and ALDH2*2 allele carriers have a much higher risk of developing esophageal cancer, especially among alcohol drinkers.

Yokoyama A; Tsutsumi E; Imazeki H; Suwa Y; Nakamura C; Yokoyama T. Contribution of the alcohol dehydrogenase-IB genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men. International Journal of Cancer 121(5): 1047-1054, 2007. (40 refs.)

The less-active homozygous alcohol dehydrogenase-IB (ADH1B*1/*1) and inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/*2) increase the risk of upper aerodigestive tract cancer (UADTC) in Japanese alcoholics. We evaluated associations between ADH1B/ALDH2 genotypes and the blood and salivary ethanol/acetaldehyde levels of 80 Japanese alcoholic men in the morning when they first visited our hospital after drinking the day before. Higher levels of ethanol persisted in the blood for longer periods in ADH1B*1/*1 carriers (n = 25) than in ADH1B*2 allele carriers after adjustment for the amount and time of the preceding alcohol consumption and body weight [median (25th-75th %): 20.5 mM (15.5-52.4) vs. below detection level [(DL-6.4), p = 0.0003]. The ethanol levels in blood and saliva were similar, but the acetaldehyde levels in saliva were strikingly higher than in the blood, and were higher in ADH1B*1/*1 carriers than in ADH1B*2 allele carriers [47.4 mu M (22.2-87.6) vs. 1.60 [(DL-26 * 3) in the saliva, p = 0.0091. The salivary acetaidehyde levels were correlated with salivary acetaldehyde production (r = 0.34, p = 0.002). The oral bacteria and yeast counts were correlated with salivary acetaldehyde production. Both the microorganisms counts and acetaldehyde production decreased after 3 weeks of abstinence, and the decreases were correlated (r = 0.35, p = 0.042). No effect of inactive ALDH2 (n = 12) on ethanol lingering the next morning was observed. In conclusion, the high salivary acetaidehyde levels in the alcoholics were partly attributable to prolonged ethanol exposure because of the less-active ADH1B and increased salivary acetaldehyde production as a result of oral microorganism overgrowth, and may explain their high risk for UADTC.

Yokoyama M; Yokoyama A; Yokoyama T; Funazu K; Hamana G; Kondo S et al. Hangover susceptibility in relation to aldehyde dehydrogenase-2 genotype, alcohol flushing, and mean corpuscular volume in Japanese workers. Alcoholism: Clinical and Experimental Research 29(7): 1165-1171, 2005. (20 refs.)

Background: A study of Asian-American students suggested a positive association between inactive ALDH2*2 and susceptibility to hangover. A biomarker for moderate-to-heavy drinking in persons with inactive aldehyde dehydrogenase-2 (ALDH2) is increased mean corpuscular volume (MCV). Methods: Associations between hangover and ALDH2 genotype, alcohol flushing, and MCV were examined for 251 Japanese workers (139 men, 112 women). Results: Inactive ALDH2*1/2*2 heterozygotes drank less alcohol than active ALDH2*1/2*1 homozygotes (p < 0.0001), but the frequency of hangover did not significantly differ between the two groups for either gender. The amount of drinking reported to lead to hangover was significantly less for male and female ALDH2*1/2*2 heterozygotes than for their ALDH2*1/2*1 homozygous counterparts (p < 0.005). The proportion of men who had hangover three times or more during the past year increased significantly with increased daily alcohol consumption in men with the ALDH2*1/2*2 genotype (p = 0.0002) but not in those with the ALDH2*1/2*1 genotype. For men who usually consumed < 44 g of ethanol/day, the median amount of drinking before hangover was significantly lower for ALDH2*1/2*2 men than for ALDH2*1/2*1 men reporting the same level of consumption. Hangover occurred with consistently high frequency among ALDH2*1/2*1 men, regardless of their daily consumption. Similar findings were observed in a comparison of men who never flushed and those who reported current or former flushing, a surrogate marker of inactive ALDH2. Assessment of hangover risk by quartiles of MCV showed that men with MCV of 96 had a significantly higher risk of hangover than did men with MCV of < 91 (odds ratio = 5.56; 95% confidence interval = 1.69-18.25). Conclusions: Inactive heterozygous ALDH2, alcohol flushing, and increased MCV were positively associated with hangover susceptibility in Japanese workers, suggesting that acetaldehyde is etiologically linked to the development of hangover.

Yokoyama A; Yokoyama T; Kumagai Y; Kato H; Igaki H; Tsujinaka T et al. Mean corpuscular volume, alcohol flushing, and the predicted risk squamous cell carcinoma of the esophagus in cancer-free Japanese men. Alcoholism: Clinical and Experimental Research 29(10): 1877-1883, 2005. (33 refs.)

Background: Because some of the causes of increased mean corpuscular volume (MCV) and esophageal squamous cell carcinoma (ESCC), including alcoholism, acetaldehyde exposure, smoking, and poor nutrition are common to both, macrocytosis has been used as a predictor of early ESCC in Japanese alcoholics. We examined whether this was also true in the Japanese general population. Methods: This study compared the MCV of 522 cancer-free Japanese men with his risk of ESCC as defined using drinking, smoking, dietary habits and aldehyde dehydrogenase-2 (ALDH2) genotype in a previous case-control study of ESCC involving them as control subjects. Results: MCV was significantly correlated with ESCC risk predicted by drinking combined with ALDH2 genotype, smoking, or fruit intake. Men at higher risk of ESCC were more frequent in the groups with higher MCV (p < 0.0001 for trend). The replies to a questionnaire about facial flushing in response to alcohol showed that the trend was more prominent in men with current/former flushing, a surrogate marker for inactive ALDH2, than in men with no flushing (p < 0.0001). In comparison with the mean risk of men with MCV <= 93 fl (lowest quartile), that of current/former flushing men with MCV >= 99 fl (highest quartile) was 6.35-fold higher, whereas that of never-flushing men with MCV >= 99 fl was 2.50-fold higher. No sensitivity and specificity of the combination of moderate-to-heavy drinking and either MCV 99 fl or current/former flushing, either 30+ pack-years or MCV >= 99 fl or either 30+ pack-years or current/former flushing for detection of high-risk persons ranking in the top 10%, was 85% and 84%, 94% and 76%, or 98% and 77%, respectively. Conclusions: MCV and alcohol flushing might be used to better select candidates to screen this high-mortality-rate cancer not only in alcoholics but also in nonalcoholic Japanese men.

Zhang FF; Hon LF; Terry MB; Lissowska J; Morabia A; Chen JB et al. Genetic polymorphisms in alcohol metabolism, alcohol intake and the risk of stomach cancer in Warsaw, Poland. International Journal of Cancer 121(9): 2060-2064, 2007. (23 refs.)

Genetic variations increasing blood levels of acetaldehyde, the first metabolite of alcohol, refrain their carriers from drinking alcohol but may also put them at increased risk of cancer because of the mutagenic and carcinogenic effect of acetaldehyde. In a population-based study of 305 cases and 428 controls in Warsaw, Poland, we evaluated the effect of polymorphisms in alcohol metabolizing genes. including ADH1B (Ex9+5C>T, Ex3+23A>G, Ex3+58A>T and Ex9+77A>G), ADH1C (EX8-56A>G and Ex6-14G>A) and ALDH2 (Ex1+82A>G), on levels of alcohol drinking and susceptibility of stomach cancer. We found that among control subjects frequency of alcohol drinking varied by alcohol metabolizing genotype. In particular, the weekly consumption of individuals carrying the AA, GA and GG genotypes of ALDH2 Ex1+82A >G polymorphism were 3.75, 2.26 and 1.53 drinks, respectively (p = 0.04). However, none of the assessed polymorphisms in these 3 genes had a measurable effect on stomach cancer risk. When stratified by ALDH2 Ex1+82A>G polymorphism, alcohol-related increases in stomach cancer risk were restricted to individuals with the AG/GG genotypes, with a more than 2-fold risk among daily drinkers (OR = 2.63, 95% CI = 1.00-6.88) and 3-fold risk (OR = 3.66, 95% CI = 1.19-11.24) among those with 40 or more drink-years. In summary, our results suggested that the ALDH2 Ex1+82 G allele may be functionally deficient in eliminating acetaldehyde and discourage alcohol drinking. Furthermore, heavy drinkers of alcohol who were genetically prone to accumulate acetaldehyde may face an increased risk of stomach cancer.

Zimatkin SM; Buben AL. Ethanol oxidation in the living brain. Alcohol and Alcoholism 42(6): 529-532, 2007. (17 refs.)

Aim: The examination of the possibility of ethanol oxidation in the brain in vivo and the evaluation of the enzyme catalase in this process. Methods: We anesthetized rats and perfused the brain with ethanol solutions through the lateral ventricle and collected the perfusate from the Cisterna magna. We determined ethanol and acetaldehyde in the perfusate by gas chromatography. Results: It was found that the passage of ethanol solution (85 and 90 mM) through the ventricular system of the rat brain (643 l/min) results in the significant (up to 98%) elimination of ethanol from the perfusing fluid and in the appearance of acetaldehyde (up-to 60 M) in the perfusate. The addition of the catalase inhibitor, aminotriazole, (10 mM) to the perfusing fluid decreased ethanol elimination significantly. Conclusions: The ethanol oxidation and AA accumulation take place in the living brain. The enzyme catalase is involved in this process.

CORK Bibliography: Alcohol Metabolism

84 citations. January 2005 to present

Prepared: March 2009

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Dakeishi M; Murata K; Sasaki M; Tamura A; Iwata T. Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers. Alcohol and Alcoholism 43(2): 143-147, 2008. (36 refs.)

Gao CM; Takezaki T; Wu JZ; Zhang XM; Cao HX; Ding JH et al. Polymorphisms of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 and colorectal cancer risk in Chinese males. World Journal of Gastroenterology 14(32): 5078-5083, 2008. (22 refs.)

Harrigan GG; Maguire G; Boros L. Metabolomics in alcohol research and drug development. Alcohol Research & Health 31(1): 26-35, 2008. (37 refs.)

Helander A; Bottcher M; Fehr C; Dahmen N; Beck O. Detection times for urinary ethyl glucuronide and ethyl sulfate in heavy drinkers during alcohol detoxification. Alcohol and Alcoholism 44(1): 55-61, 2009. (41 refs.)

Hipolito L; Sanchez-Catalan MJ; Polache A; Granero L. Induction of brain CYP2E1 changes the effects of ethanol on dopamine release in nucleus accumbens shell. Drug and Alcohol Dependence 100(1-2): 83-90, 2009. (61 refs.)

Hosono S; Matsuo K; Kajiyama H; Hirose K; Suzuki T; Hiraki A et al. Reduced risk of endometrial cancer from alcohol drinking in Japanese. Cancer Science 99(6): 1195-1201, 2008. (38 refs.)

Husemoen LLN; Fenger M; Friedrich N; Tolstrup JS; Fredriksen SB; Linneberg A. The association of ADH and ALDH gene variants with alcohol drinking habits and cardiovascular disease risk factors. Alcoholism: Clinical and Experimental Research 32(11): 1984-1991, 2008. (59 refs.)

Jelski W; Zalewski B; Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with liver cancer. Journal of Clinical Laboratory Analysis 22(3): 204-209, 2008. (20 refs.)

Kim DJ; Choi IG; Park BL; Lee BC; Ham BJ; Yoon S et al. Major genetic components underlying alcoholism in Korean population. Human Molecular Genetics 17(6): 854-858, 2008. (20 refs.)

Lowe ED; Gao GY; Johnson LN; Keung WM. Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase. Journal of Medicinal Chemistry 51(15): 4482-4487, 2008. (50 refs.)

Mello T; Ceni E; Surrenti C; Galli A. Alcohol induced hepatic fibrosis: Role of acetaldehyde. (review). Molecular Aspects of Medicine 29(1-2): 17-21, 2008. (37 refs.)

Mizoue T; Inoue M; Wakai K; Nagata C; Shimazu T; Tsuji I et al. Alcohol drinking and colorectal cancer in Japanese: A pooled analysis of results from five cohort studies. American Journal of Epidemiology 167(12): 1397-1406, 2008. (40 refs.)

Rozin AP; Attias J; Presser D; Rosenberg H; Moscovitz M; Bentur Y. Alcohol poisoning and venous hyperoxia. Toxicology Mechanisms and Methods 18(9): 745-750, 2008. (25 refs.)

Taylor RE; Raysor BR; Kwagyan J; Ramchandani VA; Kalu N; Powell-Davis M et al. Alterations in ethyl alcohol pharmacokinetics during oral consumption of malt liquor beverages in African Americans. Alcoholism: Clinical and Experimental Research 32(12): 2074-2080, 2008. (36 refs.)

Tudhope G. Alcohol Awareness Manual. London: Haynes, 2006

Verster JC. The alcohol hangover: A puzzling phenomenon. (review). Alcohol and Alcoholism 43(2): 124-126, 2008. (17 refs.)

Wolf A; Bray GA; Popkin BM. A short history of beverages and how our body treats them. Obesity Reviews 9(2): 151-164, 2008. (77 refs.)

Wurst FM; Dursteler-MacFarland KM; Auwaerter V; Ergovic S; Thon N; Yegles M et al. Assessment of alcohol use among methadone maintenance patients by direct ethanol metabolites and self-reports. Alcoholism: Clinical and Experimental Research 32(9): 1552-1557, 2008. (54 refs.)

Beulens JWJ; Rimm EB; Hendriks HFJ; Hu FB; Manson JE; Hunter DJ; Mukamal KJ. Alcohol consumption and type 2 diabetes: Influence of genetic variation in alcohol dehydrogenase. Diabetes 56(9): 2388-2394, 2007. (47 refs.)

Bongaerts BWC; de Goeij AFPM; van den Brandt PA; Weijenberg MP. Alcohol and the risk of colon and rectal cancer with mutations in the K-ras gene. Alcohol 38(3): 147-154, 2006. (24 refs.)

Bradford BU; Karnitsching J; Powell LL; Garbutt JC. Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol. Alcohol 41(4): 263-270, 2007. (35 refs.)

Bradford BU; Rusyn I. Swift increase in alcohol metabolism (SIAM): Understanding the phenomenon of hypermetabolism in liver. Alcohol 35(1): 13-17, 2005. (35 refs.)

Castro GD; de Castro CR; Maciel ME; Fanelli SL; de Ferreyra EC; Gomez MID et al. Ethanol-induced oxidative stress and acetaldehyde formation in rat mammary tissue: Potential factors involved in alcohol drinking promotion of breast cancer. Toxicology 219(1-3): 208-219, 2006. (60 refs.)

Chai YG; Oh DY; Chung EK; Kim GS; Kim L; Lee YS et al. Alcohol and aldehyde dehydrogenase polymorphisms in men with type I and type II alcoholism. American Journal of Psychiatry 162(5): 1003+, 2005. (7 refs.)

Chen YJ; Chen C; Wu DC; Lee CH; Wu CI; Lee JM et al. Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisins on esophageal cancer risks. International Journal of Cancer 119(12): 2827-2831, 2006. (32 refs.)

Clemens DL. Use of cultured cells to study alcohol metabolism. Alcohol Research & Health 29(4): 291-295, 2006. (19 refs.)

Cook TAR; Luczak SE; Shea SH; Ehlers CL; Carr LG; Wall TL. Associations of ALDH2 and ADH1B genotypes with response to alcohol in Asian Americans. Journal of Studies on Alcohol 66(2): 196-204, 2005. (65 refs.)

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Edenberg HJ. The genetics of alcohol metabolism - Role of alcohol dehydrogenase and aldehyde dehydrogenase variants. Alcohol Research & Health 30(1): 5-13, 2007. (45 refs.)

Edenberg HJ; Xuei XL; Chen HJ; Tian HJ; Wetherill LF; Dick DM et al. Association of alcohol dehydrogenase genes with alcohol dependence: A comprehensive analysis. Human Molecular Genetics 15(9): 1539-1549, 2006. (54 refs.)

Ehlers CL. Variations in ADH and ALDH in southwest California Indians. Alcohol Research & Health 30(1): 14-17, 2007. (17 refs.)

Eng MY; Luczak SE; Wall TL. ALDH2, ADH1B, and ADH1C genotypes in Asians: A literature review. Alcohol Research & Health 30(1): 22-27, 2007. (31 refs.)

Fisher SJ; Lee IJ; Swaan PW; Eddington ND. Evaluation of the effect of ethanol's toxic metabolite acetaldehyde on the gastrointestinal oligopeptide transporter, PEPT1: In vitro and in vivo studies. Alcoholism: Clinical and Experimental Research 32(1): 162-170, 2008. (57 refs.)

Gemma S; Vichi S; Testai E. Metabolic and genetic factors contributing to alcohol induced effects and fetal alcohol syndrome. (review). Neuroscience and Biobehavioral Reviews 31(2): 221-229, 2007. (53 refs.)

Goldman D; Oroszi G; O'Malley S; Anton R. COMBINE genetics study: The pharmacogenetics of alcoholism treatment response: Genes and mechanisms. Journal of Studies on Alcohol Supplement 15: 56-64, 2005. (61 refs.)

Grassi MC; Cioce AM; Giudici FD; Antonilli L; Nencini P. Short-term efficacy of Disulfiram or Naltrexone in reducing positive urinalysis for both cocaine and cocaethylene in cocaine abusers: A pilot study. Pharmacological Research 55(2): 117-121, 2007. (38 refs.)

Hendershot CS; MacPherson L; Myers MG; Carr LG; Wall TL. Psychosocial, cultural and genetic influences on alcohol use in Asian American youth. Journal of Studies on Alcohol 66(2): 185-195, 2005. (59 refs.)

Hey H; Schmedes A; Nielsen AA; Winding P; Gronbaek H. Effects of five different alcoholic drinks on patients with Crohn's disease. Scandinavian Journal of Gastroenterology 42(8): 968-972, 2007. (16 refs.)

Hines LA; Hunter DJ; Stampfer MJ; Spiegelman D; Chu NF; Rifai N et al. Alcohol consumption and high-density lipoprotein levels: The effect of ADH1C genotype, gender and menopausal status. Atherosclerosis 182(2): 293-300, 2005. (27 refs.)

Hiraki A; Matsuo K; Wakai K; Suzuki T; Hasegawa Y; Tajima K. Gene-gene and gene-environment interactions between alcohol drinking habit and polymorphisms in alcohol-metabolizing enzyme genes and the risk of head and neck cancer in Japan. Cancer Science 98(7): 1087-1091, 2007. (22 refs.)

Kapur BM; Vandenbroucke AC; Adamchik Y; Lehotay DC; Carlen PL. Formic acid, a novel metabolite of chronic ethanol abuse, causes neurotoxicity, which is prevented by folic acid. Alcoholism: Clinical and Experimental Research 31(12): 2114-2120, 2007. (73 refs.)

Kravos M; Malesic I; Levanic S. Serum alcohol dehydrogenase levels in patients with mental disorders. Clinica Chimica Acta 361(1/2): 86-94, 2005. (26 refs.)

Lee SP; Chiang CP; Lee SL; Hsia YJ; Chuang TL; Lin JC et al. Immunochemical features in the classification of human alcohol dehydrogenase family. Alcohol 39(1): 13-20, 2006. (37 refs.)

Loh EW; Lane HY; Chen CH; Chang PS; Ku LW; Wang KHT. Glutamate decarboxylase genes and alcoholism in Han Taiwanese men. Alcoholism: Clinical and Experimental Research 30(11): 1817-1823, 2006. (49 refs.)

Lorenzo A; Auguet T; Vidal F; Broch M; Olona M; Gutierrez C et al. Polymorphisms of alcohol-metabolizing enzymes and the risk for alcoholism and alcoholic liver disease in Caucasian Spanish women. Drug and Alcohol Dependence 84(2): 195-200, 2006. (28 refs.)

Loza AJM; Iglesias MTR; Diaz IP; Castellanos SC; Andrade CG; Mora MEM et al. Association of alcohol-metabolizing genes with alcoholism in a Mexican Indian (Otomi) population. Alcohol 39(2): 73-79, 2006. (56 refs.)

Lu RB; Ko HC; Lee JF; Lin WW; Huang SY; Wang TJ et al. No alcoholism-protection effects of ADH1B*2 allele in antisocial alcoholics among Han Chinese in Taiwan. Alcoholism: Clinical and Experimental Research 29(12): 2101-2107, 2005. (64 refs.)

Ma Y; Meregalli M; Hodges S; Davies N; Bogdanos DP; Fargion S. Alcohol dehydrogenase: An autoantibody target in patients with alcoholic liver disease. International Journal of Immunopathology and Pharmacology 18(1): 173-182, 2005. (32 refs.)

Martin CS; Balaban CD; McBurney DH. Tonic and phasic processes in the acute effects of alcohol. Experimental and Clinical Psychopharmacology 14(2): 209-218, 2006. (30 refs.)

Matsuda T; Yabushita H; Kanaly RA; Shibutani S; Yokoyama A. Increased DNA damage in ALDH2-deficient alcoholics. Chemical Research in Toxicology 19(10): 1374-1378, 2006. (27 refs.)

Matsuo K; Hiraki A; Hirose K; Ito H; Suzuki T; Wakai K et al. Impact of the alcohol-dehydrogenase (ADH) 1C and ADH1B polymorphisms on drinking behavior in nonalcoholic Japanese. Human Mutation 28(5): 506-510, 2007. (33 refs.)

Meier P; Seitz HK. Age, alcohol metabolism and liver disease. Current Opinion in Clinical Nutrition and Metabolic Care 11(1): 21-26, 2008. (43 refs.)

Moore S; Montane-Jaime LK; Carr LG; Ehlers CL. Variations in alcohol-metabolizing enzymes in people of East Indian and African descent from Trinidad and Tobago. Alcohol Research & Health 30(1): 28-30, 2007. (12 refs.)

Myers AL; Williams HE; Kraner JC; Callery PS. Identification of anhydroecgonine ethyl ester in the urine of a drug overdose victim. Journal of Forensic Sciences 50(6): 1481-1485, 2005. (36 refs.)

Parlesak MHU; Billinger C; Schafer HD; Wehner C; Bode JC et al. First-pass metabolism of ethanol in human beings: Effect of intravenous infusion of fructose. Alcohol 34(2/3): 121-125, 2005. (23 refs.)

Patrick KS; Straughn AB; Minhinnett RR; Yeatts SD; Herrin AE; DeVane CL et al. Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics. Clinical Pharmacology & Therapeutics 81(3): 346-353, 2007. (31 refs.)

Pavlic M; Libiseller K; Grubwieser P; Ulmer H; Sauper T; Rabl W. Another 'soberade' on the market: does Outox keep its promise? Wiener Klinische Wochenschrift 119(3-4): 104-111, 2007. (33 refs.)

Pedersen-Bjergaard U; Reubsaet JLE; Nielsen SL; Pedersen-Bjergaard S; Perrild H; Pramming S et al. Psychoactive drugs, alcohol, and severe hypoglycemia in insulin-treated diabetes: Analysis of 141 cases. American Journal of Medicine 118(3): 307-310, 2005. (27 refs.)

Pepino MY; Steinmeyer AL; Mennella JA. Lactational state modifies alcohol pharmacokinetics in women. Alcoholism: Clinical and Experimental Research 31(6): 909-918, 2007. (62 refs.)

Preedy VR; Watson R. Comprehensive Handbook of Alcohol Related Pathology. San Diego: Elsevier Science, 2005. (Chapter refs.)

Quertemont E; Grant KA; Correa M; Arizzi MN; Salamone JD; Tambour S et al. The role of acetaldehyde in the central effects of ethanol. Alcoholism: Clinical and Experimental Research 29(2): 221-234, 2005. (80 refs.)

Salme RO; Laposata M; Rajendram R; Cluette-Brown JE; Preedy VR. The total body mass of fatty acid ethyl esters in skeletal muscles following ethanol exposure greatly exceeds that found in the liver and the heart. Alcohol and Alcoholism 41(6): 598+, 2006. (38 refs.)

Scott DM; Taylor RE. Health-related effects of genetic variations of alcohol-metabolizing enzymes in African Americans. Alcohol Research & Health 30(1): 18-21, 2007. (27 refs.)

Seitz HK; Becker P. Alcohol metabolism and cancer risk. Alcohol Research & Health 30(1): 38+, 2007. (31 refs.)

Simic M; Tasic M. The relationship between alcohol elimination rate and increasing blood alcohol concentration. Calculated from two consecutive blood specimens. Forensic Science International 172(1): 28-32, 2007. (26 refs.)

Terry MB; Knight JA; Zablotska L; Wang Q; John EM; Andrulis IL et al. Alcohol metabolism, alcohol intake, and breast cancer risk: A sister-set analysis using the Breast Cancer Family Registry. Breast Cancer Research and Treatment 106(2): 281-288, 2007. (37 refs.)

Umulis DM; Gurmen NM; Singh P; Fogler HS. A physiologically based model for ethanol and acetaldehyde metabolism in human beings. Alcohol 35(1): 3-12, 2005. (24 refs.)

Wakabayashi I; Masuda H. Influence of drinking alcohol on atherosclerotic risk in alcohol flushers and non-flushers of oriental patients with type 2 diabetes mellitus. Alcohol and Alcoholism 41(6): 672-677, 2006. (36 refs.)

Wall TL. Genetic associations of alcohol and aldehyde dehydrogenase with alcohol dependence and their mechanisms of action. Therapeutic Drug Monitoring 27(6): 700-703, 2005. (72 refs.)

Wang DH; Ritchie JM; Smith EM; Zhang ZG; Turek LP; Haugen TH. Alcohol dehydrogenase 3 and risk of squamous cell carcinomas of the head and neck. Cancer Epidemiology, Biomarkers & Prevention 14(3): 626-632, 2005. (44 refs.)

Whitfield JB. Alcohol and gene interactions. Clinical and Laboratory Medicine 43(5): 480-487, 2005. (53 refs.)

Wurst FM; Dresen S; Allen JP; Wiesbeck G; Graf M; Weinmann W. Ethyl sulphate: A direct ethanol metabolite reflecting recent alcohol consumption. Addiction 101(2): 204-211, 2006. (37 refs.)

Xu BJ; Zheng YN; Sung CK. Natural medicines for alcoholism treatment: A review. Drug and Alcohol Review 24(6): 525-536, 2005. (113 refs.)

Yang SJ; Wang HY; Li XQ; Du HZ; Zheng CL; Chen HG et al. Genetic polymorphisms of ADH2 and ALDH2 association with asophageal cancer risk in southwest China. World Journal of Gastroenterology 13(43): 5760-5764, 2007. (27 refs.)

Yokoyama A; Tsutsumi E; Imazeki H; Suwa Y; Nakamura C; Yokoyama T. Contribution of the alcohol dehydrogenase-IB genotype and oral microorganisms to high salivary acetaldehyde concentrations in Japanese alcoholic men. International Journal of Cancer 121(5): 1047-1054, 2007. (40 refs.)

Yokoyama M; Yokoyama A; Yokoyama T; Funazu K; Hamana G; Kondo S et al. Hangover susceptibility in relation to aldehyde dehydrogenase-2 genotype, alcohol flushing, and mean corpuscular volume in Japanese workers. Alcoholism: Clinical and Experimental Research 29(7): 1165-1171, 2005. (20 refs.)

Lu RB; Ko HC; Lee JF; Lin WW; Huang SY; Wang TJ et al. No alcoholism-protection effects of ADH1B2 allele in antisocial alcoholics among Han Chinese in Taiwan. Alcoholism: Clinical and Experimental Research* 29(12): 2101-2107, 2005. (64 refs.)