Distribution of ADH1B, ALDH2, CYP2E1∗6, and CYP2E1∗7B genotypes in Turkish population

The most well-known metabolic pathways from ethanol to acetaldehyde include alcohol dehydrogenase (ADH) and the microsomal ethanol oxidizing system that involves cytochrome P450 2E1 (CYP2E1). Acetaldehyde is further oxidized to acetate by aldehyde dehydrogenase (ALDH). The genetic variation of ADH1B, ALDH2, and CYP2E1 is different among racial populations and cause difference in elimination rates of alcohol. The aim of this study was to determine the polymorphisms of ADH1B (rs1229984; Arg47His), ALDH2 (rs671; Glu487Lys), CYP2E1*6 (rs6413432; T7632A), and CYP2E1*7B (rs6413420; G-71T) in unrelated healthy Turkish population and compare it with other populations. ADH1B and ALDH2 polymorphisms were analyzed with an allele-specific polymerase chain reaction (PCR) assay, and CYP2E1*6 and CYP2E1*7B polymorphisms were genotyped by PCR-restriction fragment length polymorphism method. ADH1B polymorphism analysis yielded the genotype distribution as 83.9% ADH1B*1/1 and 16.1% ADH1B*1/2, and no individuals with ALDH2*1/2 and ALDH2*2/2 genotypes were found in Turkish population. The genotype frequencies for CYP2E1*6 polymorphism were found as 85.3% for homozygote common, 14.1% for heterozygote, and 0.6% for homozygote uncommon. For CYP2E1*7B polymorphism, the genotype frequencies were determined to be 86.5% G/G, 13.5% for G/T; however, no individuals with homozygote uncommon genotype were detected. According to our study results, the genotype distributions of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B in Turkish population were similar compared with Caucasian and some European populations, whereas differed significantly from East Asian populations. This study may be useful in epidemiological studies of the influence of ADH1B, ALDH2, CYP2E1*6, and CYP2E1*7B polymorphisms on diseases, including several types of cancer related to alcohol consumption and alcohol dependence.     

Effect of polymorphic metabolizing genes on micronucleus frequencies among benzene-exposed shoe workers in China

It is well-known that metabolism of benzene is required for the induction of toxicity and consequent health problems. Therefore, genetic variation in benzene (BZ) metabolism genes can influence health outcomes. However, large population studies are needed to provide more evidence for such relationship. We have conducted a large population investigation (385 BZ-exposed shoe workers and 197 matched healthy controls) on the association between inheritance of certain BZ metabolizing genes and the expression of micronuclei (MN). The latter was based on the cytokinesis-blocked MN assay. We analyzed the polymorphisms of GSTM1, GSTT1, GSTP1 (rs1695), CYP2E1 (rs3813867), CYP2E1 (rs2031920), CYP2E1 (rs6413432), mEH exon 3 (rs1051740), mEH exon 4 (rs2234922). Univariate Poisson regression analysis demonstrated that the BZ-exposed workers had significantly increased MN frequency compared with the controls (FR = 1.84, 95% CI: 1.56–2.18; P < 0.001), and showed a cumulative exposure dose–response relationship. The CYP2E1 rs3813867 mutant allele (CC + GC) (FR 1.15, 95% CI 1.02–1.29; P = 0.020) and rs2031920 variant allele (CT + TT) (FR = 1.23, 95% CI: 1.09–1.37, P < 0.01) was associated with higher MN frequency significantly compared with the wild genotype separately. Furthermore, the MN frequency in rs2031920 variant allele (CT + TT) (FR = 1.17, 95% CI: 1.04–1.31, P < 0.01) was also higher than the wild genotype when the age, gender and cumulative exposure dose was adjusted in Poisson regression. In addition, the CYP2E1, however, GSTM1null, GSTT1null, GSTP1 rs1695, rs6413432, rs1051740 and rs2234922 polymorphisms showed no association with MN frequency. Our results indicate that two promoter polymorphisms in the CYP2E1 gene, especially the rs2031920 variant allele, were involved with the BZ-induction of MN and may contribute to risk of cancer among exposed workers.     

Alcohol consumption, alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer in the Netherlands Cohort Study on diet and cancer

Within the Netherlands Cohort Study (1986), we examined associations between alcohol consumption, the alcohol dehydrogenase 1C (ADH1C) genotype, and risk of colorectal cancer (CRC). After a follow-up period of 7.3 years, 594 CRC cases with information on genotype and baseline alcohol intake were available for analyses. Adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30 g of alcohol per day with the ADH1C*2/*2 genotype were associated—although not statistically significant—with an increased risk of CRC relative to abstainers with the ADH1C*1/*1 genotype (RR: 1.91, 95% CI: 0.68, 5.34). The risk estimate in this exposure group increased slightly when compared with light drinkers of ≥0.5-<5 g/day with the ADH1C*1/*1 genotype (RR: 2.32, 95% CI: 0.80, 6.72). The interaction term however, was not statistically significant (P > .05). In subjects who reported to have consumed equal amounts of total alcohol both 5 years before baseline and at baseline, drinkers of ≥30 g of alcohol per day were associated—although not statistically significant—with an increased risk of CRC relative to abstainers (RR: 1.38, 95% CI: 0.80, 2.38). This risk estimate for high-level drinkers became stronger when compared with light drinkers (RR: 1.74, 95% CI: 1.01, 2.99). As main effect of genotype, we observed that the ADH1C*2/*2 genotype was associated with a 42% increase in risk of CRC when compared with the ADH1C*1/*1 genotype. In conclusion, both genotype and alcohol consumption were associated with an increased risk of CRC. Owing to limited statistical power, we found no apparent evidence for the ADH1C genotype as effect modifier of the relationship between alcohol intake and CRC. Nevertheless, the interaction deserves further investigation in larger genetic epidemiologic studies.     

Relationships of alcohol dehydrogenase 1B (<Emphasis Type="Italic">ADH1B</Emphasis>) and aldehyde dehydrogenase 2 (<Emphasis Type="Italic">ALDH2</Emphasis>) genotypes with alcohol sensitivity,drinking behavior and problem drinking in Japanese older men

Objectives

Many East Asians have the genetic polymorphisms rs1229984 in alcohol dehydrogenase 1B (ADH1B) and rs671 in aldehyde dehydrogenase 2 (ALDH2). Here we analyzed the relationships of the two genotypes with alcohol sensitivity, drinking behavior and problem drinking among older and younger men living in rural areas of Japan.

Methods

The subjects were 718 Japanese men aged 63.3 ± 10.8 (mean ± SD), categorized into the older (≥65 years, n = 357) and younger (<65 years, n = 361) groups. Facial flushing frequency, drinking behavior and positive CAGE results were compared among the genotypes using Bonferroni-corrected χ² test and a multivariate logistic regression analysis adjusting for age, BMI and lifestyle factors.

Results

The frequency of ‘always’ facial flushing among the ADH1B*1/*2 carriers was significantly lower than that among the ADH1B*2/*2 carriers in the older group (P < 0.01). The alcohol consumption (unit/day) in the ADH1B*1/*2 carriers tended to be higher compared with that in the ADH1B*2/*2 carriers among the older group (P = 0.050). In the younger group, no significant differences in alcohol sensitivity and drinking habits were generally found among the ADH1B genotypes. The ADH1B*1/*1 genotype tended to be positively associated with problem drinking in the older group (P = 0.080) but not in the younger group. The ALDH2 genotypes consistently and strongly affected the alcohol sensitivity, drinking behavior and problem drinking in both the younger and older group.

Conclusions

We for the first time observed a significant difference in alcohol sensitivity between ADH1B*1/*2 and ADH1B*2/*2 in older men aged 65 and above.

     

Alcohol drinking, mean corpuscular volume of erythrocytes, and alcohol metabolic genotypes in drunk drivers

Regular and irregular abuse of alcohol are global health priorities associated with diseases at multiple sites, including cancer. Mechanisms of diseases induced by alcohol are closely related to its metabolism. Among conventional markers of alcohol abuse, the mean corpuscular volume (MCV) of erythrocytes is prognostic of alcohol-related cancer and its predictivity increases when combined with functional polymorphisms of alcohol dehydrogenase (ADH1B [rs1229984] and ADH1C [rs698]) and the mitochondrial aldehyde dehydrogenase (ALDH2 [rs671]). Whether these genetic variants can influence abuse in alcohol drinking and MCV has never been examined in drunk-driving traffic offenders. We examined 149 drunk drivers, diagnosed as alcohol abusers according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition Text Revision (DSM-IV-TR) and enrolled in a probation program, and 257 social drinkers (controls), all Caucasian males. Alcohol intake was assessed according to self-reported drink-units/d and MCV unadjusted and adjusted for age, smoking, and body mass index. Multivariable models were used to compute MCV adjusted means. Genotype analyses were performed by PCR on DNA from blood. The adjusted MCV mean was higher in drunk-driving abusers than in controls (92 vs. 91 fL; P < .0001) and increased with the number of drink-units/d in both abusers and controls (P-trend = .0316 and .0089) already at intermediate quantities (0-1 vs. 2-4 drink-units/d: P = .054 and .024). Carriers of the common ADH1B*1/*1 (rs1229984) genotype were more likely to be drunk-driving abusers (P = .008), reported higher drink-units/d (P = .0126), and had larger MCV (P = .035). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with MCV. ADH1B*1/*1 polymorphism is significantly associated with being a drunk-driving abuser, higher alcohol drinking, and MCV enlargement. This suggests that drunk drivers with augmented MCV modulated by the alcohol metabolic ADH1B*1/*1 genotype may be at higher risk of driving incapability and of alcohol-related cancer.     

Regulation of Alcohol and Acetaldehyde Metabolism by a Mixture of Lactobacillus and Bifidobacterium Species in Human

Excessive alcohol consumption is one of the most significant causes of morbidity and mortality worldwide. Alcohol is oxidized to toxic and carcinogenic acetaldehyde by alcohol dehydrogenase (ADH) and further oxidized to a non-toxic acetate by aldehyde dehydrogenase (ALDH). There are two major ALDH isoforms, cytosolic and mitochondrial, encoded by ALDH1 and ALDH2 genes, respectively. The ALDH2 polymorphism is associated with flushing response to alcohol use. Emerging evidence shows that Lactobacillus and Bifidobacterium species encode alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) mediate alcohol and acetaldehyde metabolism, respectively. A randomized, double-blind, placebo-controlled crossover clinical trial was designed to study the effects of Lactobacillus and Bifidobacterium probiotic mixture in humans and assessed their effects on alcohol and acetaldehyde metabolism. Here, twenty-seven wild types (ALDH2*1/*1) and the same number of heterozygotes (ALDH2*2/*1) were recruited for the study. The enrolled participants were randomly divided into either the probiotic (Duolac ProAP4) or the placebo group. Each group received a probiotic or placebo capsule for 15 days with subsequent crossover. Primary outcomes were measurement of alcohol and acetaldehyde in the blood after the alcohol intake. Blood levels of alcohol and acetaldehyde were significantly downregulated by probiotic supplementation in subjects with ALDH2*2/*1 genotype, but not in those with ALDH2*1/*1 genotype. However, there were no marked improvements in hangover score parameters between test and placebo groups. No clinically significant changes were observed in safety parameters. These results suggest that Duolac ProAP4 has a potential to downregulate the alcohol and acetaldehyde concentrations, and their effects depend on the presence or absence of polymorphism on the ALDH2 gene.     

ADH1B与ALDH-2基因多态性与中国人群食管癌发病风险的Meta分析

目的探讨中国人乙醇脱氢酶1B(ADH1B)和乙醛脱氢酶-2(ALDH-2)的基因多态性与食管癌发病风险的关系。方法检索中外文数据库,获得有关ADH1B和ALDH-2位点的多态性与食管癌发病风险的病例-对照研究资料,对各位点以及与饮酒的交互作用进行Meta分析,得到合并的OR值及其95%CI。结果等位基因ADH1B*1和ALDH-2*2可增加食管癌的发病风险。基因型ADH1B*1/*2和ADH1B*1/*1的OR值分别为1.24(95%CI 1.10-1.41)和3.05(95%CI 1.94-4.77);基因型ALDH-2*1/*2和ALDH-2*2/*2的OR值分别为1.6(95%CI 1.01-2.03)和0.77(95%CI 0.28-2.09)。在饮酒人群中,与基因型ADH1B*2/*2相比,ADH1B*1/*2+*2/*2的OR=3.13(95%CI 2.17-4.51);与基因型ALDH-2*1/*1相比,ALDH-2*1/*2+*2/*2的OR=4.12(95%CI 1.98-8.56)。结论在中国人群中,等位基因ADH1B*1和ALDH-2*2均能增加食管癌患病的风险,且饮酒可以增加这一风险。     

Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33 mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200 μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1 > ALDH2 > ADH3 ≈ ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained unchanged. The ADH activity was also significantly reduced in hemorrhoids. ADH4 and ALDH3A1 were uniquely expressed in the squamous epithelium of anus at anorectal junctions. The allele frequencies of ADH1C*1 and ALDH2*2 were significantly higher in colorectal cancer and that of ALDH2*2 also significantly greater in hemorrhoids. In conclusion, ADH and ALDH isozymes are differentially expressed in mucosal cells of rectum and anus. The results suggest that acetaldehyde, an immediate metabolite of ethanol, may play an etiological role in pathogenesis of large bowel diseases.     

Gene-environmental interactions in alcohol-related health problems--contributions of molecular biology to behavior modifications

High alcohol sensitivity among Asians is mainly due to a genetic polymorphism in the low Km aldehyde dehydrogenase (ALDH2) gene. Strong correlations between the ALDH2 genotype and alcohol sensitivity or alcohol drinking habits have been reported. Another prevalent polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) among Asians appears to modify skin flushing reactions after exposure to ethanol but does not influence alcohol drinking behavior. Both the ADH2 and ALDH2 genotypes have been significantly correlated with the risk of alcoholism. In a Japanese occupational population, a gene-environment interaction of the ALDH2 genotype and daily hassles scores for development of problem drinking behavior was observed. Habitual drinkers with the ALDH2*1/*2 genotype had higher frequencies of sister-chromatid exchange in cultured lymphocytes and higher 8-OHdG levels in polymorphonuclear leukocytes than those with the ALDH2*1/*1 genotype. Alcoholics and heavy drinkers with the ALDH2*1/*2 genotype have been shown to have significantly elevated risks for esophageal and multiple cancers in upper digestive organs than those with the ALDH2*1/*1 genotype. In Japan, bronchial asthma patients with the ALDH2*1/*2 genotype have been shown to have a significantly elevated risk for experiencing alcohol-induced asthma compared with the ALDH2*1/*1 genotype. Providing services to determine these genotypes would be of great help for each individual to make a plan for tailor-made health promotion.     

The Role of CYP2B6*6 Gene Polymorphisms in 3,5,6-Trichloro-2-pyridinol Levels as a Biomarker of Chlorpyrifos Toxicity Among Indonesian Farmers

ObjectivesOne of the most widely used pesticides today is chlorpyrifos (CPF). Cytochrome P450 (CYP)2B6, the most prominent catalyst in CPF bioactivation, is highly polymorphic. The objective of our study was to evaluate the role of CYP2B6*6, which contains both 516G>T and 785A>G polymorphisms, in CPF toxicity, as represented by the concentration of 3,5,6-trichloro-2-pyridinol (TCPy), among vegetable farmers in Central Java, Indonesia, where CPF has been commonly used.MethodsA cross-sectional study was conducted among 132 vegetable farmers. Individual socio-demographic and occupational characteristics, as determinants of TCPy levels, were obtained using a structured interviewer-administered questionnaire and subsequently used to estimate the cumulative exposure level (CEL). TCPy levels were detected with liquid chromatography-mass spectrometry. CYP2B6*6 gene polymorphisms were analyzed using a TaqMan^® SNP Genotyping Assay and Sanger sequencing. Linear regression analysis was performed to analyze the association between TCPy, as a biomarker of CPF exposure, and its determinants.ResultsThe prevalence of CYP2B6*6 polymorphisms was 31% for *1/*1, 51% for *1/*6, and 18% for *6/*6. TCPy concentrations were higher among participants with CYP2B6*1/*1 than among those with *1/*6 or *6/*6 genotypes. CYP2B6*6 gene polymorphisms, smoking, CEL, body mass index, and spraying time were retained in the final linear regression model as determinants of TCPy.ConclusionsThe results suggest that CYP2B6*6 gene polymorphisms may play an important role in influencing susceptibility to CPF exposure. CYP2B6*6 gene polymorphisms together with CEL, smoking habits, body mass index, and spraying time were the determinants of urinary TCPy concentrations, as a biomarker of CPF toxicity.     

ADH2、ALDH2基因多态性及饮酒和胃癌关联的研究

[目的]探讨乙醇脱氢酶2(ADH2)、乙醛脱氢酶2(ALDH2)基因多态性及饮酒和胃癌的联系。[方法]采用病例对照研究的方法,利用变性高效液相色谱法(DHPLC)检测常熟市201例男性原发性胃癌患者和对照组ADH2、ALDH2基因型,结合饮酒因素分析其在胃癌发生中的作用。[结果]与携带ADH2(A/A)或ALDH2(G/G)基因型者相比,其它基因型并不增加患胃癌的危险性(P0.05),结合ADH2、ALDH2基因多态性及饮酒因素发现,即使饮酒量超过1.5 kg.年饮酒者任何基因型组合和不饮酒者携带ADH2(A/A)或ALDH2(G/G)基因型者相比,患胃癌的危险性并未增加(P0.05)。[结论]ADH2、ALDH2基因多态性与胃癌易感性无关。     

醛、醇脱氢酶基因多态性与三氯乙烯药疹样皮炎易感性的关系

目的研究醛脱氢酶、醇脱氢酶基因多态性与三氯乙烯药疹样皮炎易感性的关系。方法应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,比较108例三氯乙烯药疹样皮炎病人和145例健康三氯乙烯接触工人醛脱氢酶2(ALDH2)、醇脱氢酶2(ADH2)和醇脱氢酶3(ADH3)的基因多态性分布,并计算相对危险度(OR)。结果ADH2和ADH3基因型分布在病人与接触对照工人中无显著性差异;ALDH2变异型基因(ALDH2*1/*2+ALDH2*2/*2)频率在病人中显著低于接触对照工人(分别为27·8%和43·4%,P=0·011),使三氯乙烯药疹样皮炎的危险性显著降低(OR=0·50,95%CI=0·29~0·85)。结论高活性ALDH2可能是导致三氯乙烯药疹样皮炎个体易感性差异的原因之一。     

Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review

Possession of the fast metabolizing alleles for alcohol dehydrogenase (ADH), ADH1B*2 and ADH1C*1, and the null allele for aldehyde dehydrogenase (ALDH), ALDH2*2, results in increased acetylaldehyde levels and is hypothesized to increase the risk of head and neck cancer. To examine this association, the authors undertook a Human Genome Epidemiology review on these three genes and a pooled analysis of published studies on ADH1C. The majority of Asians had the fast ADH1B*2 and ADH1C*1 alleles, while the majority of Caucasians had the slow ADH1B*1/1 and ADH1C*1/2 genotypes. The ALDH2*2 null allele was frequently observed among Asians, though it was rarely observed in other populations. In a pooled analysis of data from seven case-control studies with a total of 1,325 cases and 1,760 controls, an increased risk of head and neck cancer was not observed for the ADH1C*1/2 genotype (odds ratio = 1.00, 95% confidence interval: 0.81, 1.23) or the ADH1C*1/1 genotype (odds ratio = 1.14, 95% confidence interval: 0.92, 1.41). Increased relative risks of head and neck cancer were reported for the ADH1B*1/1 and ALDH2*1/2 genotypes in several studies. Recommendations for future studies include larger sample sizes and incorporation of relevant ADH and ALDH genes simultaneously, as well as other genes. These considerations suggest the potential for the organization of a consortium of investigators conducting studies in this field.     

Genetic factors which regulate alcohol drinking behavior and their effects on health status]

High alcohol sensitivity common among Orientals is mainly due to genetic polymorphism in the low K(m) aldehyde dehydrogenase (ALDH2) gene. The relation of the ALDH2 genotype to alcohol sensitivity and drinking behavior was investigated in a Japanese occupational population. The frequency of alcohol-associated symptoms generally increased in the order of the typical homozygote, heterozygote, and atypical homozygote. Both drinking frequency and amounts of alcohol consumption were also significantly affected by the polymorphism. Polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) appeared to contribute to skin flushing post-alcohol exposure but not to alcohol drinking behavior. Multivariate analysis revealed that high alcohol consumption, the ALDH2*1/*1 genotype, and high daily hassles levels significantly contribute to the prevalence of those with a high problem-drinking score in an occupational population. In the study to assess the effects of the ALDH2 polymorphism and alcohol use on the induction of chromosome alterations in peripheral lymphocytes, we found that lymphocytes from habitual drinkers with the atypical ALDH2 genotypes had significantly higher frequencies of sister-chromatid exchange (SCE) than those from the typical ALDH2 genotype. We also measured acetaldehyde reversibly bound to hemoglobin (HbAA). In volunteers with the ALDH2*1/*2 genotype, the HbAA levels increased immediately after the drink and the elevated levels persisted up to 48 h. Among male workers, HbAA levels were significantly correlated with the recent alcohol consumption levels in both the ALDH2*1/*1 and ALDH2*1/*2 genotypes. However, the slope was much steeper in the ALDH2*1/*2 than in the ALDH2*1/*1. SCE and HbAA may be utilized as a good biomarker for health problems in the atypical ALDH2 genotype. Further extensive studies are required for evaluation of the interactive effects of genetic and environmental factors on alcohol-related health problems.     

Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol

Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mm NAD⁺. Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (K_is) ranging from 0.90 mm (ADH2) to 20 mm (ADH1A), and the intercept inhibition constants (K_ii) ranging from 1.4 mm (ADH1C allozymes) to 19 mm (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (K_is = 3.0 mm and K_ii = 2.2 mm), but competitive inhibition for ALDH1A1 (K_is = 0.96 mm). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2–0.5 mm) and physiologically relevant concentrations of ethanol (10 mm) and acetaldehyde (10 μm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12–26%) and ADH2 (14–28%) in the liver and small intestine, ADH4 (15–31%) in the stomach, and ALDH1A1 (16–33%) and ALDH2 (8.3–19%) in all 3 tissues. The results suggest that inhibition by acetaminophen of hepatic and gastrointestinal FPM of ethanol through ADH and ALDH pathways might become significant at higher, subtoxic levels of acetaminophen.     

Interaction of the Effects of Alcohol Drinking and Polymorphisms in Alcohol-Metabolizing Enzymes on the Risk of Female Breast Cancer in Japan

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 carcinogenesis of alcohol-induced breast cancer.Key words: breast cancer, alcohol drinking, acetaldehyde, polymorphisms in alcohol-metabolizing enzyme genes, case–control study     

Is ADH1C genotype relevant for the cardioprotective effect of alcohol?

The cardioprotective effect of ethanol has been suggested to be linked to one of the ethanol metabolizing enzymes (ADH1C), which constitutes a high V_max and a low V_max variant. This has been demonstrated in some studies, while others have not been able to replicate the findings. The aim of the present study was to investigate the relation between the different ADH1C genotypes, death from coronary heart disease (CHD) and alcohol in a material larger than the previously published studies. Eight hundred CHD deaths as well as 1303 controls were genotyped for the high V_max (γ1) and the low V_max (γ2) ADH1C variant. Information of alcohol use was available for all subjects. Multiple logistic regression analyses was used to study if the decreased risk of death from CHD in alcohol consuming subjects was more pronounced in subjects homozygous for the γ2 allele (γ2γ2 subjects) compared to γ1γ1 and γ1γ2 subjects. The odds ratio (OR) for death from CHD in alcohol consumers compared to abstainers was similar in the genotype groups, i.e., 0.62 (95% CI: 0.43–0.88) in γ1γ1 subjects and 0.62 (95% CI: 0.42–0.91) in γ2γ2 subjects. Also when stratifying the results by gender and when dividing alcohol consumers into different alcohol consumption groups, there was no difference in the OR between the different genotype groups. This study, which included the largest study group published so far, failed to find any link between the ADH1C genotype and the cardioprotective effects of alcohol.     

Association of alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotypes with fasting plasma glucose levels in Japanese male and female workers

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 ADH2*1/1 genotype than in those with the other genotypes, but there was no significant difference in the FPG level between the men with and without ALDH2*1/1 genotype. In contrast, the women with ALDH2*1/1 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 ADH2*1/1 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.     

Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population

ObjectivesAntituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients.MethodsCYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis.ResultsA total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P = 0.039, OR = 0.097, 95% CI: 0.011–0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P = 0.020, OR = 0.522, 95% CI: 0.301–0.903).ConclusionsThis study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result.     

青海藏族人群ADH3、ALDH2基因多态性及其与饮酒行为的关系

目的 了解青海藏族男性乙醇脱氢酶3(ADH3)和乙醛脱氢酶2(ALDH2)基因多态性分布及其与饮酒行为的关系.方法 采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对ADH3和ALDH2基因型进行检测;采用回顾性问卷调查研究对象的饮酒行为.结果 等位基因ADH3*2和ALDH2*2在藏族人群中的比例分别为7.79％和22.21％;不饮酒组中等位基因ALDH2*2、ADH3*1频率高于饮酒者;危险饮酒组中等位基因ALDH2*2、ADH3*1频率低于安全饮酒者.结论 ADH3、ALDH2基因与青海藏族男性人群饮酒行为有关.