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CORK Bibliography: Alcohol Metabolism

41 citations. January 2009 to present

Prepared: March 2012

Abraham J; Balbo S; Crabb D; Brooks PJ. Alcohol metabolism in human cells causes DNA damage and activates the Fanconi Anemia-breast cancer susceptibility (FA-BRCA) DNA damage Response Network. Alcoholism: Clinical and Experimental Research 35(12): 2113-2120, 2011. (36 refs.)

Background: We recently reported that exposure of human cells in vitro to acetaldehyde resulted in the activation of the Fanconi anemiabreast cancer susceptibility (FA-BRCA) DNA damage response network. Methods: To determine whether intracellular generation of acetaldehyde from ethanol metabolism can cause DNA damage and activate the FA-BRCA network, we engineered HeLa cells to metabolize alcohol by expression of human alcohol dehydrogenase (ADH) 1B. Results: Incubation of HeLa-ADH1B cells with ethanol (20 mM) resulted in acetaldehyde accumulation in the media, which was prevented by co-incubation with 4-methyl pyrazole (4-MP), a specific inhibitor of ADH. Ethanol treatment of HeLa-ADH1B cells produced a 4-fold increase in the acetaldehyde-DNA adduct and N 2-ethylidene-dGuo and also resulted in the activation of the FA-BRCA DNA damage response network, as indicated by a monoubiquitination of FANCD2 and phosphorylation of BRCA1. Ser 1524 was identified as 1 site of BRCA1 phosphorylation. The increased levels of DNA adducts, FANCD2 monoubiquitination, and BRCA1 phosphorylation were all blocked by 4-MP, indicating that acetaldehyde, rather than ethanol itself, was responsible for all 3 responses. Importantly, the ethanol concentration we used is within the range that can be attained in the human body during social drinking. Conclusions: Our results indicate that intracellular metabolism of ethanol to acetaldehyde results in DNA damage, which activates the FA-BRCA DNA damage response network.

Ahn KS; Abdiev S; Rahimov B; Malikov Y; Bahramov S; Okada R et al. Alcohol dehydrogenase 1B and aldehyde dehydrogenase 2 polymorphisms in Uzbekistan. Asian Pacific Journal of Cancer Prevention 10(1): 17-20, 2009. (18 refs.)

The alcohol dehydrogenase 1B (ADH1B) *2 (47His) allele and the aldehyde dehydrogenase 2 (ALDH2) *2 (487Lys) allele are seen among some Asian peoples, but rare among other ethnic groups. This study examined the allele frequencies in the Uzbekistan Republic, which is located in Central Asia. Subjects were derived from a case-control study on peptic ulcer disease, which included 161 Uzbeks and 23 Russians. They were enrolled at the Republic Research Center of Emergency Medicine located in the capital, Tashkent City. Genotyping was performed for ADH1B Arg47His and ALDH2 Glu487Lys with a polymerase chain reaction with confronting two-pair primers. The frequency for the ADH1B *2 allele was similar among cases and controls. The ALDH2 *2 allele was rare in both. Among 161 Uzbeks, the ADH1B *2 allele frequency was 0.286 (95% confidence interval, 0.237-0.338) and for the ALDH2 *2 allele was 0.016 (0.005-0.036), while among the 23 Russians the figures were 0.083 (0.024-0.208) and 0.000 (0.000-0.077), respectively. There were no significant differences in drinking habits among individuals with different genotypes, although ALDH2 *2*2 genotype was not observed. The present study demonstrated that ADH1B *2 allele frequency among Uzbeks was closer to that among Caucasians than East Asians, some Uzbeks also demonstrating the ALDH2 *2 allele.

Arolfo MP; Overstreet DH; Yao L; Fan PD; Lawrence AJ; Tao GX et al. Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcoholism: Clinical and Experimental Research 33(11): 1935-1944, 2009. (43 refs.)

Background: Inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However, daidzin can reduce drinking in some rodents without necessarily increasing acetaldehyde. Therefore, a selective ALDH-2 inhibitor might affect other metabolic factors involved in regulating drinking. Methods: Aldehyde dehydrogenase 2 inhibitors were synthesized based on the co-crystal structure of ALDH-2 and daidzin. We tested the efficacy of a highly selective reversible ALDH-2 inhibitor, CVT-10216, in models of moderate and high alcohol drinking rats. We studied 2-bottle choice and deprivation-induced drinking paradigms in Fawn Hooded (FH) rats, operant self-administration in Long Evans (LE), FH, and inbred P (iP) rats and in cue-induced reinstatement in iP rats. We also assayed blood acetaldehyde levels as well as dopamine (DA) release in the nucleus accumbens (NAc) and tested possible rewarding/aversive effects of the inhibitor in a conditioned place preference (CPP) paradigm. Results: CVT-10216 increases acetaldehyde after alcohol gavage and inhibits 2-bottle choice alcohol intake in heavy drinking rodents, including deprivation-induced drinking. Moreover, CVT-10216 also prevents operant self-administration and eliminates cue-induced reinstatement of alcohol seeking even when alcohol is not available (i.e., no acetaldehyde). Alcohol stimulates DA release in the NAc, which is thought to contribute to increased drinking and relapse in alcoholism. CVT-10216 prevents alcohol-induced increases in NAc DA without changing basal levels. CVT-10216 does not show rewarding or aversive properties in the CPP paradigm at therapeutic doses. Conclusion: Our findings suggest that selective reversible ALDH-2 inhibitors may have therapeutic potential to reduce excessive drinking and to suppress relapse in abstinent alcoholics.

Baek IH; Lee BY; Kwon KI. Influence of dissolved oxygen concentration on the pharmacokinetics of alcohol in humans. Alcoholism: Clinical and Experimental Research 34(5): 834-839, 2010. (14 refs.)

Background: Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation. We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5% v/v). Methods: Blood alcohol concentrations (BACs) were determined by converting breath alcohol concentrations. Breath samples were collected every 30 min when the BAC was higher than 0.015%, 20 min at BAC < 0.015%, 10 min at BAC < 0.010%, and 5 min at BAC < 0.006%. Results: The high dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p < 0.05). In analyzing pharmacokinetic parameters, AUC(inf) and K-el of the high oxygen groups were lower than in the normal oxygen group, while C-max and T-max were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC(inf) and t(1/2) was expected to be reduced in the high oxygen group compared to the normal oxygen group. Conclusions: In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol. Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol-related side effects and accidents.

Boyles AL; DeRoo LA; Lie RT; Taylor JA; Jugessur A; Murray JC et al. Maternal alcohol consumption, alcohol metabolism genes, and the risk of oral clefts: A population-based case-control study in Norway, 1996-2001. American Journal of Epidemiology 172(8): 924-931, 2010. (36 refs.)

Heavy maternal alcohol consumption during early pregnancy increases the risk of oral clefts, but little is known about how genetic variation in alcohol metabolism affects this association. Variants in the alcohol dehydrogenase 1C (ADH1C) gene may modify the association between alcohol and clefts. In a population-based case-control study carried out in Norway (1996-2001), the authors examined the association between maternal alcohol consumption and risk of oral clefts according to mother and infant ADH1C haplotypes encoding fast or slow alcohol-metabolizing phenotypes. Subjects were 483 infants with oral cleft malformations and 503 control infants and their mothers, randomly selected from all other livebirths taking place during the same period. Mothers who consumed 5 or more alcoholic drinks per sitting during the first trimester of pregnancy had an elevated risk of oral cleft in their offspring (odds ratio (OR) = 2.6, 95% confidence interval (CI): 1.4, 4.7). This increased risk was evident only in mothers or children who carried the ADH1C haplotype associated with reduced alcohol metabolism (OR= 3.0, 95% CI: 1.4, 6.8). There was no evidence of alcohol-related risk when both mother and infant carried only the rapid-metabolism ADH1C variant (OR = 0.9, 95% CI: 0.2, 4.1). The teratogenic effect of alcohol may depend on the genetic capacity of the mother and fetus to metabolize alcohol.

Cabrera MAS; Dip RM; Furlan MO; Rodrigues SL. Use of drugs that act on the cytocrhrome P450 system in the elderly. Clinics 64(4): 273-278, 2009. (28 refs.)

OBJECTIVES: The objective of this study was to analyze medications that act on the cytochrome P450 (CYP450) enzymatic system and are used daily by non-institutionalized elderly individuals. METHODS: A cross-sectional population-based study of elderly individuals (>= 60 years old) was conducted. All continuously used medications with hepatic metabolism via CYP450 that are classified as substrates, inducers or inhibitors were considered. For the analysis, elderly individuals were stratified according to age groups, and hepatic metabolism activity due to daily alcohol consumption and smoking were considered. RESULTS: Elderly individuals (396 in total: 222 women and 174 men) between 60 and 95 years of age (mean: 72.1) were assessed. Use of drugs that act on CYP450 was identified in 61.6% of the subjects. Drug use was observed among 16.2% of the subjects: three drugs among 9.8% and four or more among 6.3% of the subjects. The metabolic activities of the drugs used were classified as substrates (58.8%), inhibitors (14.9%), and inducers (4.3%). The main drugs used were beta-blockers and statins (as substrates), proton pump inhibitors and fluoxetine (as inhibitors), and prednisone and carbamazepine (as inducers). CONCLUSIONS: The results demonstrate that the elderly use high levels of medications that act on CYP450, thereby increasing the risk of drug interactions in a group that is already vulnerable to adverse drug effects.

Canova C; Richiardi L; Merletti F; Pentenero M; Gervasio C; Tanturri G et al. Alcohol, tobacco and genetic susceptibility in relation to cancers of the upper aerodigestive tract in northern Italy. Tumori 96(1): 1-10, 2010. (46 refs.)

Aims and background. Each year in Italy there are approximately 14,000 new cases and 7,000 deaths from cancer of the upper aerodigestive tract, which includes malignant tumors originating from the oral cavity, pharynx, larynx and esophagus. Established etiological factors include tobacco consumption and heavy alcohol drinking. The study of single nucleotide polymorphisms in upper aerodigestive tract cancer etiology may help to identify high-risk subgroups and to better understand the pathways leading to the development of these cancers. Methods. Italian results on about 500 cases and 500 controls from a large case-control study (ARCAGE) conducted in 10 European countries are presented with the major objectives of updating results on the effects of alcohol and tobacco consumptions in northern Italy, investigating the role of genetic variation with regard to the metabolism of alcohol and carcinogens from tobacco smoke, and evaluating possible interactions of these single nucleotide polymorphisms with these carcinogens. Results. The present study confirmed the importance of tobacco smoking and alcohol drinking as the main risk factors for upper aerodigestive tract cancers, indicating that about 68% of cancers among populations in northern Italy can be attributed to the combination of these risk factors. Significant associations between metabolizing phase I genes (CYP1A1 and CYP2A6), phase II genes (GSTA2) and upper aerodigestive tract cancers were found. A polymorphism of ADH1C has been associated with an increased risk of upper aerodigestive tract cancers, suggesting that the less rapid alcohol metabolizers are more susceptible to upper aerodigestive tract cancer risk. Conclusions. Our results suggest that the ADH1Callele modifies the carcinogenic dose response for alcohol in the upper aerodigestive tract, giving rise to a gene-environment interaction. The role of genes as possible modifiers of life-style risks seems the most reliable.

Chase JR; Poolman MG; Fell DA. Contribution of NADH increases to ethanol's inhibition of retinol oxidation by human ADH isoforms. Alcoholism: Clinical and Experimental Research 33(4): 571-580, 2009. (50 refs.)

A decrease in retinoic acid levels due to alcohol consumption has been proposed as a contributor to such conditions as fetal alcohol spectrum diseases and ethanol-induced cancers. One molecular mechanism, competitive inhibition by ethanol of the catalytic activity of human alcohol dehydrogenase (EC 1.1.1.1) (ADH) on all-trans-retinol oxidation has been shown for the ADH7 isoform. Ethanol metabolism also causes an increase in the free reduced nicotinamide adenine dinucleotide (NADH) in cells, which might reasonably be expected to decrease the retinol oxidation rate by product inhibition of ADH isoforms. To understand the relative importance of these two mechanisms by which ethanol decreases the retinol oxidation in vivo we need to assess them quantitatively. We have built a model system of 4 reactions: (1) ADH oxidation of ethanol and NAD(+), (2) ADH oxidation of retinol and NAD(+), (3) oxidation of ethanol by a generalized Ethanol(oxidase) that uses NAD(+), (4) NADH(oxidase) which carries out NADH turnover. Using the metabolic modeling package ScrumPy, we have shown that the ethanol-induced increase in NADH contributes from 0% to 90% of the inhibition by ethanol, depending on (ethanol) and ADH isoform. Furthermore, while the majority of flux control of retinaldehyde production is exerted by ADH, Ethanol(oxidase) and the NADH(oxidase) contribute as well. Our results show that the ethanol-induced increase in NADH makes a contribution of comparable importance to the ethanol competitive inhibition throughout the range of conditions likely to occur in vivo, and must be considered in the assessment of the in vivo mechanism of ethanol interference with fetal development and other diseases.

Chen YC; Peng GS; Wang MF; Tsao TP; Yin SJ. Polymorphism of ethanol-metabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences. Chemico-Biological Interactions 178(1-3): 2-7, 2009. (34 refs.)

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for metabolism of ethanol. Both ADH and ALDH exhibit genetic polymorphisms among racial populations. Functional variant alleles ADH1B*2 and ALDH2*2 have been consistently replicated to show protection against developing alcohol dependence. Multiple logistic regression analyses suggest that ADH1B*2 and ALDH2*2 may independently influence the risk for alcoholism. It has been well documented that homozygosity of ALDH2*2 almost fully protects against developing alcoholism and that the heterozygosity only affords a partial protection to varying degrees. Correlations of blood ethanol and acetaldehyde concentrations, cardiovascular hemodynamic responses, and subjective perceptions have been investigated in men with different combinatorial ADH1B and ALDH2 genotypes following challenge with ethanol for a period of 130 min. The pharmacokinetic and pharmacodynamic consequences indicate that acetaldehyde, rather than ethanol, is primarily responsible for the observed alcohol sensitivity reactions, suggesting that the full protection by ALDH2*2/*2 can be ascribed to the intense unpleasant physiological and psychological reactions caused by persistently elevated blood acetaldehyde after ingesting a small amount of alcohol and that the partial protection by ALDH2*1/*2 can be attributed to a faster elimination of acetaldehyde and the lower accumulation in circulation. ADH1B polymorphism does not significantly contribute to buildup of the blood acetaldehyde. Physiological tolerance or innate insensitivity to acetaldehyde may be crucial for development of alcohol dependence in alcoholics carrying ALDH2*2.

Chiang CP; Wu CW; Lee SP; Chung CC; Wang CW; Lee SL et al. Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human pancreas: Implications for pathogenesis of alcohol-induced pancreatic injury. Alcoholism: Clinical and Experimental Research 33(6): 1059-1068, 2009. (48 refs.)

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are major enzymes responsible for metabolism of ethanol. Genetic polymorphisms of ADH1B, ADH1C, and ALDH2 occur among racial populations. The metabolic effect and metabolites contribute to pathogenesis of pancreatic injury. The goal of this study was to determine the functional expressions and cellular localization of ADH and ALDH families in human pancreas. Fifty five surgical specimens of normal pancreas as well as 15 samples each for chronic pancreatitis and pancreatic cancer from archival formalin-fixed paraffin-embedded tissue specimens were investigated. Class-specific antibodies were prepared by affinity chromatographies from rabbit antisera raised against recombinant human ADH1C1, ADH4, ADH5, ADH7, ALDH1A1, ALDH2, and ALDH3A1. The isozyme expression patterns of ADH/ALDH were identified by isoelectric focusing, and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting, and the cellular localizations were detected by immunohistochemistry and histochemistry. At 33 mM ethanol, pH 7.5, the activities were significantly different between allelic phenotypes of ADH1B. The activity of ALDH2-inactive phenotypes was slightly lower than ALDH2-active phenotypes at 200 mu M acetaldehyde. The protein contents were in the following decreasing order: ALDH1A1, ALDH2, ADH1, and ADH5. ADH1B was detected in the acinar cells and ADH1C in the ductular, islet, and stellate cells. The expression of ADH1C appeared to be increased in the activated pancreatic stellate cells in chronic pancreatitis and pancreatic cancer. Alcohol dehydrogenase and ALDH family members are differentially expressed in the various cell types of pancreas. ADH1C may play an important role in modulation of activation of pancreatic stellate cells.

Dettling A; Preiss A; Skopp G; Haffner HT. The influence of the luteal and follicular phases on major pharmacokinetic parameters of blood and breath alcohol kinetics in women. Alcohol 44(4): 315-321, 2010. (28 refs.)

Drink tests involving 14 women were carried out to determine the effects of the menstrual cycle phases on the pharmacokinetics of ethanol. One experiment was carried out in the follicular phase of the cycle and another in the luteal phase, with the estradiol, progesterone, and testosterone levels being determined in both cases. The target concentration was a final blood alcohol concentration (BAC) of approximately 0.08 g%. After drinking was completed, concurrent BAC and breath alcohol concentration (BrAC) measurements were carried out at intervals of 10-20 min. The ethanol elimination rate was determined by calculating a linear function in the part of the slope that was clearly linear. In addition, the c(0) and Widmark factors r were calculated. In 10 of the volunteers, who had a normal increase in progesterone in the luteal phase, the average hourly elimination rate beta(60) in the follicular phase amounted to 0.0194 +/- 0.0020 g%/h (BAC) and 0.0975 +/- 0.0068 mg/L/h (BrAC), and in the luteal phase to 0.0193 +/- 0.0031 g%/h (BAG) and 0.1026 +/- 0.0101 mg/L/h (BrAC). There was no significant difference. Other pharmacokinetic parameters (c(0) concentrations, Widmark factors r, distribution volumes, maximal BAC, mean absorption rate, time until the peak concentrations were reached) also revealed no significant differences between the blood and breath alcohol levels of the luteal and follicular phases. In addition, no significant correlations were observed between the absolute progesterone level and the respective elimination rates beta(60).

Ding JH; Li SP; Cao HX; Wu JZ; Gao CM; Liu YT et al. Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotypes, alcohol drinking and the risk for esophageal cancer in a Chinese population. Journal of Human Genetics 55(2): 97-102, 2010. (19 refs.)

To investigate the relationship among alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) genetic polymorphisms, alcohol consumption and the susceptibility to esophageal cancer in a Chinese population, we conducted a case-control study with 221 cases and 191 population-based controls in the Taixing city of Jiangsu Province of China. ADH2 and ALDH2 genotypes were examined using PCR and denaturing high-performance liquid chromatography. Alcohol drinkers with the ALDH2 A allele showed a significantly increased risk of esophageal cancer compared with drinkers with the ALDH2 G/G genotype (odds ratio (OR) = 3.08, 95% confidence interval (CI): 1.65-5.78) or nondrinkers with any genotype (OR = 3.05, 95% CI: 1.49-6.25). Drinkers with the ALDH2 A allele and a cumulative amount of alcohol consumption >= 2.5 (kg * years) were at a significantly higher risk of developing esophageal cancer (OR = 11.93, 95% CI: 3.17-44.90) compared with individuals with ALDH2 G/G genotypes and a cumulative amount of alcohol consumption <2.5 (kg * years). A dose-dependent positive result was found between cumulative amount of alcohol consumption and risk of esophageal cancer in individuals carrying the ALDH2 A allele (P = 0.023) and the homozygous ALDH2 G allele (P = 0.047). Compared with individuals carrying both ALDH2 G/G and ADH2 A/A alleles and with a cumulative amount of alcohol consumption <2.5 (kg* years), drinkers carrying both ALDH2 A and ADH2 G alleles and with a cumulative amount of alcohol consumption >= 2.5 (kg* years) showed a significantly elevated risk of esophageal cancer (OR = 53.15, 95% CI: 4.24-666.84). This result suggests that to help lower their risk for esophageal cancer, persons carrying the ALDH2 A allele should be encouraged to reduce their consumption of alcoholic beverages.

Druesne-Pecollo N; Tehard B; Mallet Y; Gerber M; Norat T; Hercberg S et al. Alcohol and genetic polymorphisms: Effect on risk of alcohol-related cancer. (review). Lancet Oncology 10(2): 173-180, 2009. (75 refs.)

Public health guidelines aim to limit the consumption of alcoholic beverages worldwide and the subsequent health burden. In particular, alcohol consumption is an avoidable risk factor for cancer. In human beings, ethanol in alcoholic drinks is mainly oxidised in the liver by alcohol dehydrogenases to acetaldehyde, and is further detoxified to acetate by aldehyde dehydrogenases. Functional variants in genes involved in alcohol metabolism result in differences between individuals in exposure to carcinogenic acetaldehyde, suggesting a possible interaction of genetic susceptibility and alcohol exposure in cancer. We reviewed available studies of the combined effects of alcohol drinking and genetic polymorphisms on alcohol-related cancer risk. Most available data were for polymorphisms in alcohol and folate metabolism. We give an overview of published studies on the combined effects of alcohol drinking and polymorphisms in genes for alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), cytochrome P450 2E1, and methylenetetrahydrofolate reductase on the risk of alcohol-related cancer. Current data lend support to a role of polymorphisms ADH1B and ALDH2 combined with alcohol consumption in cancer. Other available data are insufficient or inconclusive, highlighting the need for additional studies.

Fujita G; Nishida Y. E ffect of a small dose of alcohol on driving-related behavior of Japanese who self-reported facial flush and nonflushing. Perceptual and Motor Skills 109(3): 651-663, 2009. (25 refs.)

About half of northeastern Asians lack ALDH2 (Acetaldehyde Dehydrogenase 2), an enzyme involved in alcohol metabolism. People with deficient ALDH2 often experience facial flushing after drinking a small dose of alcohol. The present study examined the effect of a small dose of alcohol on driving-related behavior of northeastern Asians (Japanese). Participants were 9 Japanese flushers and 12 Japanese nonflushers. They were evaluated using a driving simulator and self-report of intoxication after ingesting 0.6g/kg or 0.4g/kg of alcohol or a placebo. Facial flushers were more likely to experience subjective feelings of intoxication than were nonflushers. There were no significant differences between facial flashers and nonflushers in blood alcohol concentration and choice reaction time to visual stimuli. Despite having different subjective feelings of intoxication, facial flashers and nonflushers were equally impaired after having ingested equal amounts of alcohol per body weight.

Hallinan R; Crettol S; Agho K; Attia J; Besson J; Croquette-Krokar M et al. Cannabis and benzodiazepines as determinants of methadone trough plasma concentration variability in maintenance treatment: A transnational study. European Journal of Clinical Pharmacology 65(11): 1113-1120, 2009. (45 refs.)

To assess tobacco, alcohol, cannabis and benzodiazepine use in methadone maintenance treatment (MMT) as potential sources of variability in methadone pharmacokinetics. Trough plasma (R)- and (S)-methadone concentrations were measured on 77 Australian and 74 Swiss MMT patients with no additional medications other than benzodiazepines. Simple and multiple regression analyses were performed for the primary metric, plasma methadone concentration/dose. Cannabis and methadone dose were significantly associated with lower 24-h plasma (R)- and (S)-methadone concentrations/dose. The models containing these variables explained 14-16% and 17-25% of the variation in (R)- and (S)-methadone concentration/dose, respectively. Analysis of 61 patients using only CYP3A4 metabolised benzodiazepines showed this class to be associated with higher (R)-concentration/dose, which is consistent with a potential competitive inhibition of CYP3A4. Cannabis use and higher methadone doses in MMT could in part be a response to --or a cause of- more rapid methadone clearance. The effects of cannabis and benzodiazepines should be controlled for in future studies on methadone pharmacokinetics in MMT.

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.

Hendershot CS; Neighbors C; George WH; McCarthy DM; Wall TL; Liang TB et al. ALDH2, ADH1B and alcohol expectancies: Integrating genetic and learning perspectives. Psychology of Addictive Behaviors 23(3): 452-463, 2009. (82 refs.)

The present study evaluated associations of ALDH2 and ADH1B genotypes with alcohol expectancies and drinking behavior in a sample of Asian American young adults. In addition to assessing global alcohol expectancies, the authors developed a measure of physiological expectancies to evaluate an expectancy phenotype specific to the mechanism by which ALDH2 and ADH1B variations presumably influence drinking behavior. Compared with individuals with the ALDH2*1/*1 genotype, those with the ALDH2*2 allele reported greater negative alcohol expectancies, greater expectancies for physiological effects of alcohol and lower rates of alcohol use. ADH1B was not associated with alcohol expectancies or drinking behavior. Hierarchical models showed that demographic factors, ALDH2 genotype, and expectancy variables explained unique variance in drinking outcomes. Mediation tests showed significant indirect effects of ALDH2 on drinking frequency and peak lifetime consumption through expectancies. These results provide support for influences of genetic factors and alcohol sensitivity on alcohol-related learning and suggest the importance of developing biopsychosocial models of drinking behavior in Asian Americans.

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.

Hoiseth G; Morini L; Polettini A; Christophersen A; Morland J. Blood kinetics of ethyl glucuronide and ethyl sulphate in heavy drinkers during alcohol detoxification. Forensic Science International 188(1-3): 52-56, 2009. (28 refs.)

Studies of ethyl glucuronide (EtG) blood kinetics have so far been performed on healthy volunteers with ingestion of low to moderate doses of ethanol. These data are not necessarily transferable to heavy drinkers where the consumed doses of ethanol are much higher. The aim of this study was to investigate the pharmacokinetics of EtG and ethyl sulphate (EtS) in blood in heavy drinkers after termination of alcohol ingestion. Sixteen patients from an alcohol withdrawal clinic were included directly after admission. Time of end of drinking, estimated daily intake of ethanol (EDI) and medical history were recorded. Three to five blood samples over 20-43 h were collected from each patient subsequent to admission. The median EDI was 172 g (range 60-564). The first sample was collected median 2.5 h after end of drinking (range 0.5-23.5). Two patients had levels of EtG and EtS below LOQ in all samples, the first collected 19.25 and 23.5 h after cessation of drinking, respectively. Of the remaining 14 patients, one subject, suffering from both renal and hepatic disease, showed concentrations of EtG and EtS substantially higher than the rest of the material. This patient's initial value of EtG was 17.9 mg/L and of EtS 5.9 mg/L, with terminal elimination half lives of 11.9 h for EtG and 12.5 h for EtS. Among the remaining 13 patients, the initial median values were 0.7 g/L (range 0-3.7) for ethanol, 1.7 mg/L (range 0.1-5.9) for EtG and 0.9 mg/L (range 0.1-1.9) for EtS. Elimination occurred with a median half-life of 3.3 h for EtG (range 2.6-4.3) and 3.6 h for EtS (range 2.7-5.4). In conclusion, elimination of EtG in heavy drinkers did not significantly differ from healthy volunteers, and EtS appeared to have similar elimination rate. In the present work, there was one exception to this, and we propose that this could be explained by the patient's renal disease, which would delay excretion of these conjugated metabolites.

Homann N; Konig IR; Marks M; Benesova M; Stickel F; Millonig G et al. Alcohol and colorectal cancer: The role of alcohol dehydrogenase 1C polymorphism. Alcoholism: Clinical and Experimental Research 33(3): 551-556, 2009. (44 refs.)

Chronic alcohol consumption is a risk factor for colorectal cancer. Animal experiments as well as genetic linkage studies in Japanese individuals with inactive acetaldehyde dehydrogenase leading to elevated acetaldehyde concentrations following ethanol ingestion support the hypothesis that acetaldehyde may be responsible for this carcinogenic effect of alcohol. In Caucasians, a polymorphism of alcohol dehydrogenase 1C (ADH1C) exists resulting in different acetaldehyde concentrations following ethanol oxidation. To evaluate whether the association between alcohol consumption and colorectal tumor development is modified by ADH1C polymorphism, we recruited 173 individuals with colorectal tumors diagnosed by colonoscopy and 788 control individuals without colorectal tumors. Genotyping was performed using genomic DNA extracted from whole blood followed by polymerase chain reaction. Genotype ADH1C*1/1 was more frequent in patients with alcohol-associated colorectal neoplasia compared to patients without cancers in the multivariate model controlling for age, gender, and alcohol intake (odds ratio = 1.674, 95% confidence interval = 1.110-2.524, 2-sided p from Wald test = 0.0139). In addition, the joint test of the genetic effect and interaction between ADH1C genotype and alcohol intake (2-sided p = 0.0007) indicated that the difference in ADH1C*1 polymorphisms between controls and colorectal neoplasia is strongly influenced by the alcohol consumption and that only individuals drinking more than 30 g ethanol per day with the genotype ADH1C*1/1 had an increased risk for colorectal tumors. These data identify ADH1C homozygosity as a genetic risk marker for colorectal tumors in individuals consuming more than 30 g alcohol per day and emphasize the role of acetaldehyde as a carcinogenic agent in alcohol-related colorectal carcinogenesis.

Jung JG; Kim JS; Oh MK. The role of the flushing response in the relationship between alcohol consumption and insulin resistance. Alcoholism: Clinical and Experimental Research 34(10): 1699-1704, 2010. (32 refs.)

Background: Facial flushing responses to drinking, because of intolerance to alcohol, are observed in some people, especially Asians. This study examined the role of flushing responses in the relationship between alcohol consumption and insulin resistance (IR). Methods: Participants in this cross-sectional analysis included 624 Korean men (80 nondrinkers, 306 nonflushing drinkers, and 238 flushing drinkers) who were free of cardiovascular disease and diabetes. Data on the flushing response to drinking and alcohol consumption were collected from medical records. IR was estimated using the Homeostasis Model Assessment (HOMA(IR)). On the basis of comparisons with nondrinkers, the risk of IR according to the quantity of alcohol consumed per week was analyzed among nonflushers and flushers. Results: After adjusting for age, exercise status, smoking status, BMI, waist circumference, blood pressure, high-density lipoprotein cholesterol, and triglycerides using a logistic regression model, we found a low risk of IR among nonflushers who consumed < 4 drinks (1 drink = 14 g of alcohol) per week (OR = 0.3). In contrast, a higher risk of IR was associated with nonflushers who consumed > 20 drinks per week (OR = 3.5). On the other hand, only a higher risk of IR was associated with flushers who consumed > 12 drinks per week (> 12 to 20 drinks: OR = 4.7; > 20 drinks: OR = 3.5). Conclusions: The amount of drinking associated with the development of IR in flushers was lower than in nonflushers. Additionally, no positive effect of moderate drinking on IR was observed in flushers. The findings support acetaldehyde-derived mechanisms in the development of alcohol-related IR.

Karahanian E; Quintanilla ME; Tampier L; Rivera-Meza M; Bustamante D; Gonzalez-Lira V et al. Ethanol as a prodrug: Brain metabolism of ethanol mediates its reinforcing effects. Alcoholism: Clinical and Experimental Research 35(4): 606-612, 2011. (39 refs.)

Background: While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis. Methods: The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Results: Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (-94%p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption. Conclusions: The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.

Kawase T; Matsuo K; Hiraki A; Suzuki T; Watanabe M; Iwata H et al. Interaction of the effects of alcohol drinking and polymorphisms in alcohol-metabolizing enzymes on the risk of female breast cancer in Japan. Journal of Epidemiology 19(5): 244-250, 2009. (35 refs.)

Background: Epidemiological studies consistently indicate that alcoholic beverages are an independent risk factor for female breast cancer. Although the mechanism underlying this effect remains unknown, the predominant hypothesis implicates mutagenesis via the ethanol metabolite acetaldehyde, whose impact on the carcinogenesis of several types of cancer has been shown in both experimental models and molecular epidemiological studies. Many of the epidemiological Studies have investigated genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) His48Arg and aldehyde dehydrogenase-2 (ALDH2) Glu504Lys, because of the strong impact these polymorphisms have on exposure to and accumulation of acetaldehyde. With regard to breast cancer, however, evidence is scarce. Methods: To clarify the impact on female breast cancer risk of the interaction of the effects of alcohol consumption and polymorphisms in the alcohol-metabolizing enzymes ADH1B and ALDH2, we conducted a case-control study of 456 newly and histologically diagnosed breast cancer cases and 912 age- and menopausal status-matched noncancer controls. Gene-gene and gene-environment interactions between individual and combined ADH1B and ALDH2 gene polymorphisms and alcohol consumption were evaluated. Results: Despite sufficient statistical power, there was no significant impact of ADH1B and ALDH2 on the risk of breast cancer. Neither was there any significant gene-environment interactions between alcohol drinking and polymorphisms in ADH1B and ALDH2. Conclusions: Our findings do not support the hypothesis that acetaldehyde is the main contributor to the careinogenesis of alcohol-induced breast cancer.

Khan AJ; Husain Q; Choudhuri G; Parmar D. Association of polymorphism in alcohol dehydrogenase and interaction with other genetic risk factors with alcoholic liver cirrhosis. Drug and Alcohol Dependence 109(1-3): 190-197, 2010. (41 refs.)

The association of polymorphism of alcohol dehydrogenase (ADH) and its interaction with genes involved in the generation and detoxification of free radicals such as cytochrome P4502E1 (CYP2E1) and glutathione S-transferases M1 (GSTM1) were studied with alcoholic liver cirrhosis. The study included 175 alcoholic cirrhotic patients, 140 non-alcoholic cirrhotic patients, 255 non-alcoholic controls and 140 alcoholic controls. Our data revealed that the ADH1C*1/*1 genotype exhibited significant association with alcoholic liver cirrhosis while ADH1B genotypes did not show any significant association. A much higher risk to alcoholic liver cirrhosis was observed in patients carrying a combination of wild genotypes of ADH1C (ADH1C1/*1) and variant genotype of ADH1B (ADH1B*2/.2) or CYP2E1 (CYP2E1*5B) or null genotype of GSTM1. Our data suggest a role for the interaction amongst the genes involved in metabolizing alcohol and in generating and detoxifying free radicals with susceptibility to alcoholic liver cirrhosis.

Kim SK; Lee SI; Shin CJ; Son JW; Ju G. The genetic factors affecting drinking behaviors of Korean young adults with variant aldehyde dehydrogenase 2 genotype. Psychiatry Investigation 7(4): 270-277, 2010. (24 refs.)

Objective We determined whether aldehyde dehydrogenase 2 (ALDH2) activity alters the way in which drinking behaviors are affected by gene polymorphisms of other alcohol-metabolizing enzymes and serotonin-related proteins. Methods Through a follow-up survey with a cohort comprising 551 university freshmen over a period of 6 years, we examined the genetic factors affecting drinking behaviors. In 2000, drinking behaviors were assessed and tryptophan hydroxylase (TPH) and ALDH2 gene polymorphisms were determined. Drinking behaviors were repeated in 2006 (n=150), and the gene polymorphisms of ADH1B, ADH1C, CYP2E1, 5-HTR2A 1438A/G, and 5-HTR2A IVS2 were also determined. Results In 2000, the variant and wild-type ALDH2 groups exhibited little difference in terms of drinking frequency and problem drinking. Furthermore, some genotypes influenced only the variant group: ADH1B*2/*2 was associated with a lower drinking frequency, and CYP2E1 c2 allele was associated with an increased risk of problem drinking. In 2006, drinking frequency and risk of problem drinking were significantly lower in the variant group than in the wild-type group. However, the TPH AA genotype disturbed that difference, meaning that the subjects in the variant group had developed a similar level of risk of problem drinking to that in the wild-type group. Conclusion Korean university freshmen who were identified as a variant group drank as frequently as those in the wild-type group. For the subsequent 6 years they drank less frequently, thus decreasing the risk of problem drinking. However, that frequency drop was interrupted in those with gene polymorphisms such as ADH1B*1, CYP2E1 c2, and TPH A.

Lee SY; Hahn CY; Lee JF; Chen SL; Chen SH; Yeh TL et al. MAOA-uVNTR polymorphism may modify the protective effect of ALDH2 gene against alcohol dependence in antisocial personality disorder. Alcoholism: Clinical and Experimental Research 33(6): 985-990, 2009. (58 refs.)

Antisocial alcoholism is related to dopamine and serotonin which are catalyzed by monoamine oxidase A (MAOA) and acetaldehyde dehydrogenase 2 (ALDH2). The objective of this study is to determine whether the interaction between the MAOA and the ALDH2 genes is associated with subjects with antisocial personality disorder (ASPD) having alcoholism. A total of 294 Han Chinese men in Taiwan including 132 ASPD with alcoholism (Antisocial ALC) and 162 without alcoholism (Antisocial Non-ALC) were recruited in this study. Alcohol dependence and ASPD were diagnosed according to DSM-IV criteria. Genotypes of ALDH2 and MAOA-uVNTR were determined using PCR-RFLP. A significant difference of ALDH2 polymorphisms (p = 3.39E-05), but not of MAOA, was found among the 2 study groups. However, only after the stratification of the MAOA-uVNTR (variable number of tandem repeat located upstream) 3-repeat, a significant association between Antisocial Non-ALC and ALDH2*1/*2 or *2/*2 genotypes was shown (p = 1.46E-05; odds ratio = 3.913); whereas stratification of MAOA-uVNTR 4-repeat revealed no association. Multiple logistic regression analysis further revealed significant interaction of MAOA and ALDH2 gene in antisocial ALC (odds ratio = 2.927; p = 0.032). The possible interaction of MAOA and ALDH2 gene is associated with Antisocial ALC in Han Chinese males in Taiwan. However, the protective effects of the ALDH2*2 allele against alcoholism might disappear in subjects with ASPD and carrying MAOA-uVNTR 4-repeat allele in the Han Chinese male population.

Li H; Borinskaya S; Yoshimura K; Kal'ina N; Marusin A; Stepanov VA et al. Refined geographic distribution of the oriental ALDH2504Lys (nee 487Lys) variant. Annals of Human Genetics* 73(Part 3): 335-345, 2009. (42 refs.)

Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.

Liu JX; Zhou ZF; Hodgkinson CA; Yuan QP; Shen PH; Mulligan CJ et al. Haplotype-based study of the association of alcohol-metabolizing genes with alcohol dependence in four independent populations. Alcoholism: Clinical and Experimental Research 35(2): 304-316, 2011. (63 refs.)

Background: Ethanol is metabolized by 2 rate-limiting reactions: alcohol dehydrogenases (ADH) convert ethanol to acetaldehyde that is subsequently metabolized to acetate by aldehyde dehydrogenases (ALDH). Approximately 50% of East Asians have genetic variants that significantly impair this pathway and influence alcohol dependence (AD) vulnerability. We investigated whether variation in alcohol metabolism genes might alter the AD risk in four non-East Asian populations by performing systematic haplotype association analyses to maximize the chances of capturing functional variation. Methods: Haplotype-tagging SNPs were genotyped using the Illumina GoldenGate platform. Genotypes were available for 40 SNPs across the ADH genes cluster and 24 SNPs across the two ALDH genes in four diverse samples that included cases (lifetime AD) and controls (no Axis 1 disorders). The case control sample sizes were the following: Finnish Caucasians: 232, 194; African Americans: 267, 422; Plains American Indians: 226, 110; and Southwestern American (SW) Indians: 317, 72. Results: In all four populations, as well as HapMap populations, 5 haplotype blocks were identified across the ADH gene cluster: (i) ADH5-ADH4; (ii) ADH6-ADH1A-ADH1B; (iii) ADH1C; (iv) intergenic; (v) ADH7. The ALDH1A1 gene was defined by 4 blocks and ALDH2 by 1 block. No haplotype or SNP association results were significant after correction for multiple comparisons; however, several results, particularly for ALDH1A1 and ADH4, replicated earlier findings. There was an ALDH1A1 block 1 and 2 (extending from intron 5 to the 3' UTR) yin yang haplotype (haplotypes that have opposite allelic configuration) association with AD in the Finns driven by SNPs rs3764435 and rs2303317, respectively, and an ALDH1A1 block 3 (including the promoter region) yin yang haplotype association in SW Indians driven by 5 SNPs, all in allelic identity. The ADH4 SNP rs3762894 was associated with AD in Plains Indians. Conclusions: The systematic evaluation of alcohol-metabolizing genes in four non-East Asian populations has shown only modest associations with AD, largely for ALDH1A1 and ADH4. A concentration of signals for AD with ALDH1A1 yin yang haplotypes in several populations warrants further study.

Mennella JA; Pepino MY. Breast pumping and lactational state exert differential effects on ethanol pharmacokinetics. Alcohol 44(2): 141-148, 2010. (44 refs.)

Prior research revealed that breast stimulation altered the way the lactating body handles alcohol. Its effects depended upon when it occurred relative to drinking. The goal of the present study was to determine whether breast pumping works independently of the physiological and metabolic changes that accompany lactation. To this end, we tested 12 women when they were exclusively breastfeeding 3-5-month-old infants and then again several months after lactation had ceased. Subjects were randomly assigned to one of two groups that differed in the timing of breast pumping relative to drinking a 0.4 g/kg dose of alcohol: one group breast pumped 0.6 h after drinking (pumped after group) and the other pumped 1 h before drinking (pumped before group). For each reproductive stage, subjects were tested on 2 separate days, consuming a standardized meal 1 h before drinking during 1 test day and remaining fasted during the other. Breath alcohol concentrations (BrAC) and temperature readings were obtained before and at fixed intervals after drinking. Pumping before drinking significantly decreased BrAC during both reproductive stages, whereas pumping after drinking resulted in different BrAC time curves during lactation when compared with after lactation. That is, levels were significantly lower during the descending phase of the time curve during than after lactation. The interactions between pumping and reproductive stage were most apparent during fed condition. Furthermore, women were more sensitive to hypothermic effects of both fasting and drinking alcohol during lactation. These findings add to the growing literature that lactating women metabolize alcohol differently, in part, due to the frequent breast stimulation during breastfeeding and the pronounced physiological changes that accompany one of the most energetically costly mammalian activities.

Mochly-Rosen D; Zakhari S. Focus on: the cardiovascular system: What did we learn from the French (paradox)? Alcohol Research & Health 33(1-2): 76-86, 2010. (112 refs.)

Although heavy alcohol consumption has deleterious effects on heart health, moderate drinking is thought to have cardioprotective effects, reducing the risk of coronary artery disease and improving prognosis after a myocardial infarction. It still is unclear, however, if this effect can be achieved with all types of alcoholic beverages and results from the alcohol itself from other compounds found in alcoholic beverages, or both. For example, the polyphenolic compound resveratrol, which is found particularly in red wine, can reduce the risk of atherosclerosis; however, it is not clear if the resveratrol levels present in wine are sufficient to achieve this result. Alcohol itself contributes to cardioprotection through several mechanisms. For example, it can improve the cholesterol profile, increasing the levels of "good" cholesterol and reducing the levels of "bad" cholesterol Alcohol also may contribute to blood clot dissolution and may induce a phenomenon called pre-conditioning, whereby exposure to moderate alcohol levels (like short bouts of blood supply disruption [i.e., ischemia]), and result in reduced damage to the heart tissue after subsequent prolonged ischemia. Finally, the enzyme aldehyde dehydrogenase (ALDH) 2, which is involved in alcohol metabolism, also may contribute to alcohol-related cardioprotection by metabolizing other harmful aldehydes that could damage the heart muscle.

Moss AC; Dyer KR; Albery IP; Allsop S; Kypri K; Erskine J et al. Alcohol pharmacokinetics, decision making and folk wisdom: A reply to Moxnes and Jensen (2009) (editorial). Drug and Alcohol Dependence 109(1-3): 1-3, 2010. (19 refs.)

Moxnes and Jensen (2009) present a study of decision making under conditions of uncertainty using a computerised simulation of alcohol pharmacokinetics. In their article, they conclude that their findings challenge the 'folk wisdom' that advises against drinking on an empty stomach. We contend that this is a problematic conclusion for three reasons: (1) the study and findings presented in their paper are simply not sufficient to allow one to, even tentatively, draw such a conclusion; (2) the conclusion is contrary to basic pharmacological knowledge concerning alcohol absorption, metabolism and the implications for peak blood alcohol concentration: and (3) the implications for understanding the process of decision making while alcohol intoxicated are not considered in the study. The Moxnes and Jensen (2009) study did not involve alcohol administration and is therefore an examination of decision making in situations of uncertainty rather than a specific exploration of drinking-related decision making. Recent formulations of the effects of alcohol on cognitive processing would lead to different conclusions than those presented by Moxnes and Jensen (2009). We conclude by suggesting our understanding of the implications of the study.

Moxnes E; Jensen L. Complex alcohol pharmacokinetics: A response to Moss et al. (editorial). Drug and Alcohol Dependence 109(1-3): 4-5, 2010. (0 refs.)

The commentary by Moss et al. (2010) disagrees with policy recommendations we did not give. Our main conclusions were that "Our study warrants further studies... [and]... implies a modification of the 'folk wisdom' of not drinking on an empty stomach." Our conclusions were based on a laboratory experiment where we found that juvenile subjects behaved according to a simple feedback rule when making drinking decisions. This rule led them to overshoot intended levels of drunkenness. For further research we suggested a diagnostic information treatment to test effects on real drinking behavior. Moss et al. misinterpret our discussion of the 'folk wisdom' and their comments strengthen our claim that this is a complex issue that requires further studies.

Osby U; Liljenberg J; Kockum I; Gunnar A; Terenius L. Genes and alcohol. European Psychiatry 25(5, special issue): 281-283, 2010. (18 refs.)

The negative effects of excessive alcohol use include dependence, psychiatric co-morbidity and increased risk for suicide. A dominating risk factor is heritage. A large number of studies have addressed the genetic basis, either "candidate genes" in the brain reward system, or searched for unknown genes in family studies by linkage analysis. It is clear that no single gene polymorphism is of use in preventive medicine. A consistent finding, however, is that polymorphism in the alcohol dehydrogenase cluster and other metabolic pathways are of some relevance on a population basis, suggesting a link between alcohol toxicity in general and dependence. An emerging concern is potential gender differences as women, who are generally more sensitive, acquire male drinking habits.

Pautassi RM; Camarini R; Quadros IM; Miczek KA; Israel Y. Genetic and environmental influences on ethanol consumption: Perspectives from preclinical research. (review). Alcoholism: Clinical and Experimental Research 34(6): 976-987, 2010. (122 refs.)

Background: Alcohol use disorders (abuse and dependence, AUD) are multifactorial phenomena, depending on the interplay of environmental and genetic variables. Method: This review describes current developments in animal research that may help (a) develop gene therapies for the treatment of alcoholism, (b) understand the permissive role of stress on ethanol intake, and (c) elucidate why exposure to ethanol early in life is associated with a greater risk of AUD. Results: The polymorphisms found in liver alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) affect the elimination of ethanol and the susceptibility to ethanol intake. A highly active ADH protects against alcoholism, an effect related to a presteady state burst in arterial acetaldehyde. Social stressors, such as repeated early maternal separation or social defeat, exert a permissive effect on ethanol intake, perhaps by altering the normal development of the hypothalamic-pituitary-adrenal axis. Ethanol exposure during gestation, infancy, or adolescence increases the likelihood of AUD later in life. Early perception of ethanol's positive and negative (anti-anxiety) reinforcing effects may play a role in this phenomenon. Conclusions: The review underscores the advantages of using preclinical animal models of AUD and highlights points of intersection between the topics to help design a more integrated approach for the study of alcohol-related problems.

Rainero I; Rubino E; Gallone S; Fenoglio P; Negro E; De Martino P et al. Cluster headache is associated with the alcohol dehydrogenase 4 (ADH4) gene. Headache 50(1): 92-98, 2010. (38 refs.)

Background/Objectives: Alcohol is a well-known trigger factor for cluster headache attacks during the active phases of the disease. The alcohol dehydrogenase (ADH) pathway, which converts alcohol to the toxic substance acetaldehyde, is responsible for most of the alcohol breakdown in the liver. Humans have 7 ADH genes, tightly clustered on chromosome 4q21-q25, that encode different ADH isoforms. The ADH4 gene encodes the class II ADH4 pi subunit, which contributes, in addition to alcohol, to the metabolization of a wide variety of substrates, including retinol, other aliphatic alcohols, hydroxysteroids, and biogenic amines. The purpose of this study was to investigate the association of genetic variants within the ADH4 gene with cluster headache susceptibility and phenotype. Methods: A total of 110 consecutive unrelated cluster headache patients and 203 age- and sex-matched healthy controls of Caucasian origin were involved in the study. Patients and controls were genotyped for 2 bi-allelic single nucleotide polymorphisms (SNPs) of the ADH4 gene: SNP1 - rs1800759 and SNP2 - rs1126671. Allele, genotype, and haplotype frequencies of the examined polymorphisms were compared between cases and controls. Results: Genotype frequencies of the rs1126671 polymorphism resulted significantly different between cluster headache patients and controls (KH2 = 10.269, P = .006). The carriage of the AA genotype, in comparison with remaining genotypes, was associated with a significantly increased disease risk (OR = 2.33, 95% CI: 1.25-4.37). Haplotype analysis confirmed the association between the ADH4 gene and the disease. No association between different clinical characteristics of cluster headache and the examined polymorphisms was found. Conclusion: Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease.

Rose ME; Grant JE. Alcohol-induced blackout phenomenology, biological basis, and gender differences. (review). Journal of Addiction Medicine 4(2): 61-73, 2010. (149 refs.)

Blackouts from acute alcohol ingestion are defined as the inability to recall events that occurred during a drinking episode and are highly prevalent in both alcoholic and nonalcoholic populations. This article reviews the clinical manifestations, epidemiology, risk factors, cognitive impairment, and neurobiology associated with alcohol-induced blackout, with special emphasis on the neurochemical and neurophysiological basis, and gender differences. Two types of blackout have been identified: en bloc, or complete inability to recall events during a time period, and fragmentary, where memory loss is incomplete. The rapidity of rise in blood alcohol concentration is the most robust predictor of blackout. Alcohol impairs different brain functions at different rates, and cognitive and memory performance are differentially impaired by ascending versus descending blood alcohol concentration. Cognitive and memory impairment occurs before motor impairment, possibly explaining how a drinker appearing fully functional can have little subsequent memory. Blackouts are caused by breakdown in the transfer of short-term memory into long-term storage and subsequent retrieval primarily through dose-dependent disruption of hippocampal CA1 pyramidal cell activity. The exact mechanism is believed to involve potentiation of gamma-aminobutyric acid-alpha-mediated inhibition and interference with excitatory hippocampal N-methyl-D-aspartate receptor activation, resulting in decreased long-term potentiation. Another possible mechanism involves disrupted septohippocampal theta rhythm activity because of enhanced medial septal area gamma-aminobutyric acid-ergic neurotransmission. Women are more susceptible to blackouts and undergo a slower recovery from cognitive impairment than men, due in part to the effect of gender differences in pharmacokinetics and body composition on alcohol bioavailability.

Sherva R; Rice JP; Neuman RJ; Rochberg N; Saccone NL; Bierut LJ. Associations and interactions between SNPs in the alcohol metabolizing genes and alcoholism phenotypes in European Americans. Alcoholism: Clinical and Experimental Research 33(5): 848-857, 2009. (42 refs.)

Alcohol dependence is a major cause of morbidity and mortality worldwide and has a strong familial component. Several linkage and association studies have identified chromosomal regions and/or genes that affect alcohol consumption, notably in genes involved in the 2-stage pathway of alcohol metabolism. Here, we use multiple regression models to test for associations and interactions between 2 alcohol-related phenotypes and SNPs in 17 genes involved in alcohol metabolism in a sample of 1,588 European American subjects. The strongest evidence for association after correcting for multiple testing was between rs1229984, a nonsynonymous coding SNP in ADH1B, and DSM-IV symptom count (p = 0.0003). This SNP was also associated with maximum number of drinks in 24 hours (p = 0.0004). Each minor allele at this SNP predicts 45% fewer DSM-IV symptoms and 18% fewer max drinks. Another SNP in a splice site in ALDH1A1 (rs8187974) showed evidence for association with both phenotypes as well (p = 0.02 and 0.004, respectively), but neither association was significant after accounting for multiple testing. Minor alleles at this SNP predict greater alcohol consumption. In addition, pairwise interactions were observed between SNPs in several genes (p = 0.00002). We replicated the large effect of rs1229984 on alcohol behavior, and although not common (MAF = 4%), this polymorphism may be highly relevant from a public health perspective in European Americans. Another SNP, rs8187974, may also affect alcohol behavior but requires replication. Also, interactions between polymorphisms in genes involved in alcohol metabolism are likely determinants of the parameters that ultimately affect alcohol consumption.

Takeuchi F; Isono M; Nabika T; Katsuya T; Sugiyama T; Yamaguchi S et al. Confirmation of ALDH2 as a major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population. Circulation Journal 75(4): 911-918, 2011. (39 refs.)

Background: Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population. Methods and Results: In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers. The associated loci without redundancy of linkage disequilibrium were further examined in the stage-2 general population panel comprising 2,794 drinkers (>= once per week), 1,521 chance drinkers (Copyright 2011, Japanese Circulation Society

Tan EC; Lim L; Leong JY; Lim JY; Lee A; Yang J et al. Alcohol and aldehyde dehydrogenase polymorphisms in Chinese and Indian populations. Substance Use & Misuse 45(1/2): 1-14, 2010. (29 refs.)

The association between two functional polymorphisms in alcohol dehydrogenase (ADH2/ADH1B) and aldehyde dehydrogenase (ALDH2) genes and alcohol dependence was examined in 182 Chinese and Indian patients undergoing treatment for alcohol dependence and 184 screened control subjects front Singapore. All subjects were screened by, the Alcohol Use Disorders Identification Test (AUDIT). Patients were also administered the Severity of Alcohol Dependence Questionnaire (SADQ). Polymorphisms were genotyped by allele-specific polymerase chain reaction and selected genotypes confirmed by DNA sequencing or restriction fragment length polymorphism. Our results showed that frequencies of ADH1B*2 and ALDH2*2 were higher in controls compared to alcohol-dependent subjects for both Chinese and Indians. Frequencies of these two alleles were also higher in the 104 Chinese controls compared to the 80 Indian controls. None of the eight Chinese who were homozygous for both protective alleles was alcohol dependent. The higher frequencies of the protective alleles could explain the lower rate of alcohol dependence in Chinese.

Tolstrup JS; Gronbaek M; Tybjaerg-Hansen A; Nordestgaard BG. Alcohol intake, alcohol dehydrogenase genotypes, and liver damage and disease in the Danish general population. American Journal of Gastroenterology 104(9): 2182-2188, 2009. (25 refs.)

OBJECTIVES: We tested the hypothesis that alcohol, alone and in combination with alcohol dehydrogenase (ADH) 1B and ADH1C genotypes, affects liver damage and disease in the general population. METHODS: Information on alcohol intake and on liver disease was obtained from 9,080 men and women from the Copenhagen City Heart Study. Biochemical tests for the detection of liver damage were specific for alanine aminotransferase (ALT), aspartate aminotransferase (AST)-to-ALT ratio (AST/ALT), gamma-glutamyl transpeptidase (gamma-GT), albumin, bilirubin, alkaline phosphatase, coagulation factors, and erythrocyte volume. RESULTS: Increasing alcohol intake was associated with increasing erythrocyte volume, AST/ALT, and levels of ALT, gamma-GT, albumin, bilirubin, coagulation factors, and with decreasing levels of alkaline phosphatase. Multifactorially adjusted hazard ratios for alcoholic liver disease overall were 0.9 (95% confidence interval (CI), 0.6-1.4), 1.4 (0.8-2.5), 1.8 (0.9-3.5), and 4.1 (2.5-7.0) for an alcohol intake of 1-13, 14-20, 21-27, and >= 28 drinks per week, respectively, compared with drinking <1 drink per week (P for trend <0.0001); the corresponding hazard ratios for alcoholic liver cirrhosis were 1.7 (0.6-4.7), 2.0 (0.8-7.1), 6.5 (2.0-21), and 13 (4.6-37) (P for trend <0.0001). ADH1B and ADH1C genotypes were not associated with and did not modify the effect of alcohol on biochemical tests or risk of liver disease. CONCLUSIONS: Increasing alcohol intake from none to low (1-6 drinks per week) through to moderate (7-20 drinks per week) and excessive intake (>= 21 drinks per week) leads to stepwise increases in signs of liver damage with no threshold effect, and to an increased risk of liver disease. The minor changes in biochemical tests for low alcohol intake may not account for subclinical liver disease.

Zhang YM; Ren J. ALDH2 in alcoholic heart diseases: Molecular mechanism and clinical implications. (review). Pharmacology & Therapeutics 132(1): 86-95, 2011. (158 refs.)

Alcoholic cardiomyopathy is manifested as cardiac hypertrophy, disrupted contractile function and myofibrillary architecture. An ample amount of clinical and experimental evidence has depicted a pivotal role for alcohol metabolism especially the main alcohol metabolic product acetaldehyde, in the pathogenesis of this myopathic state. Findings from our group and others have revealed that the mitochondrial isoform of aldehyde dehydrogenase (ALDH2), which metabolizes acetaldehyde, governs the detoxification of acetaldehyde formed following alcohol consumption and the ultimate elimination of alcohol from the body. The ALDH2 enzymatic cascade may evolve as a unique detoxification mechanism for environmental alcohols and aldehydes to alleviate the undesired cardiac anomalies in ischemia-reperfusion and alcoholism. Polymorphic variants of the ALDH2 gene encode enzymes with altered pharmacokinetic properties and a significantly higher prevalence of cardiovascular diseases associated with alcoholism. The pathophysiological effects of ALDH2 polymorphism may be mediated by accumulation of acetaldehyde and other reactive aldehydes. Inheritance of the inactive ALDH2*2 gene product is associated with a decreased risk of alcoholism but an increased risk of alcoholic complications. This association is influenced by gene-environment interactions such as those associated with religion and national origin. The purpose of this review is to recapitulate the pathogenesis of alcoholic cardiomyopathy with a special focus on ALDH2 enzymatic metabolism. It will be important to dissect the links between ALDH2 polymorphism and prevalence of alcoholic cardiomyopathy, in order to determine the mechanisms underlying such associations. The therapeutic value of ALDH2 as both target and tool in the management of alcoholic tissue damage will be discussed.