ADH1C*2 allele is associated with alcohol dependence and elevated liver enzymes in Trinidad and Tobago.

Variants in alcohol dehydrogenase (ADH) genes differ between ethnic groups and have, in some studies, been found to be associated with alcohol dependence and alcoholic liver disease. This study sought to determine whether an association exists between ADH (ADH1C previously ADH3, ADH1B*2 previously ADH2*2) genotypes, alcohol dependence, drinking history, and liver function tests in the two major ethnic groups of Trinidad and Tobago (TT). One hundred and forty-five alcohol-dependent individuals of both East Indian (Indo-TT) and African (Afro-TT) ancestry, and 108 controls matched by age, sex, and education participated in the study. Serum levels of alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and gamma-glutamyltransferase (GGT) as well as presence of HIV, hepatitis B surface antigen, and anti-hepatitis C virus antibody were determined. There was a significant difference in the distribution of ADH1C allele polymorphisms between the ethnic groups (P<.0001). Forty-three percent of the Indo-TT were found to have one ADH1C*2 allele and 5% were homozygous, whereas, only 23% of Afro-TT had one allele and one was homozygous. Only three individuals had an ADH1B*2 allele (one Indo-TT alcohol dependent, two Indo-TT controls). The ADH1C*2 allele was significantly associated with alcohol dependence overall and within Indo-TT ancestry, however, it was not associated with current or heaviest alcohol consumption levels. Individuals with at least one ADH1C*2 allele also had significantly elevated levels of ALP (P<.02) and GGT (P<.02) as compared to individuals homozygous for ADH1C*. Additionally, GGT levels were also found to be elevated (P<.02) within Indo-TT alcohol dependents with at least one ADH1C*2 allele but not within the Afro-TT alcohol dependents with that allele. A linear regression that included alcohol dependence and levels of alcohol consumption confirmed that levels of serum GGT were significantly associated with the ADH1C*2 genotype. These results suggest that ADH1C polymorphisms are associated with alcohol dependence and alcohol associated elevations of liver enzymes in a population with a low frequency of ADH1B2 alleles.     

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.     

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.     

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.     

Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.

Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) modulates enhancement of nicotinic receptor function by ethanol. To identify the association between the CfoI polymorphism of the CHRNA4 and alcoholism, we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism (n = 127) and Korean control subjects without alcoholism (n = 185) with polymerase chain reaction-restriction fragment length polymorphism methods. We were able to detect the association between the CfoI polymorphism of the CHRNA4 and alcoholism in Korean patients (genotype P = .023; allele frequency P = .047). The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes, such as alcohol metabolism-related genes [alcohol dehydrogenase 2 (ADH2), aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 3 (ADH3), and cytochrome P450 2E1 (CYP2E1)] and mu-opioid receptor gene (OPRM1), were studied. The polymorphisms of ADH2, ALDH2, and CYP2E1 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism, but ADH3 and OPRM1 did not differ between the two groups.     

酒精代谢酶基因型在日本双生子中的分布

目的为预防酒精相关性疾病发生,调查了酒精代谢酶控制基因在日本双生子中的分布。方法以饱和酚法提取ＤＮＡ,应用限制性片段长度多态性分析技术检测了９２个日本双生子的酒精脱氢酶２（ＡＤＨ２）和乙醛脱氢酶２（ＡＬＤＨ２）基因型,根据基因型差异筛选敏感个体。结果ＡＤＨ２和ＡＬＤＨ２基因分布符合Ｈａｒｄｙｗｅｉｎｂｅｒｇ等式。ＡＤＨ２基因的３种基因型分别是ＡＤＨ２１／ＡＤＨ２１（１．１％）、ＡＤＨ２１／ＡＤＨ２２（４４．６％）和ＡＤＨ２２／ＡＤＨ２２（５４．３％）。ＡＬＤＨ２的基因型分别为ＡＬＤＨ２１／ＡＬＤＨ２１（４１．３％）、ＡＬＤＨ２１／ＡＬＤＨ２２（３９．１％）和ＡＬＤＨ２２／ＡＬＤＨ２２（１９６％）。ＡＤＨ２和ＡＬＤＨ２基因频率分别为０．２５５、０．７４５和０６０９、０３９１。结论异常纯合的ＡＤＨ２基因和纯合的ＡＬＤＨ２基因占优势。个体携有ＡＤＨ２１／ＡＤＨ２２和ＡＬＤＨ２１／ＡＬＤＨ２１、ＡＤＨ２２／ＡＤＨ２２和ＡＬＤＨ２１／ＡＬＤＨ２１者可视为敏感个体。     

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。     

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。     

Investigation of alcohol metabolizing enzyme genes in Chinese alcoholics with avascular necrosis of hip joint,pancreatitis and cirrhosis of the liver

AIMS AND METHODS: Alcoholism may cause a range of diseases including avascular necrosis of the hip joint (AVN), cirrhosis of the liver, pancreatitis and oesophageal carcinoma. Chinese alcoholic patients diagnosed with AVN have a higher incidence of cirrhosis than of acute pancreatitis or oesophageal cancer. Thus, the aim of this study was to investigate genetic differences in polymorphisms of the alcohol-metabolizing enzymes ADH2, ADH3, ALDH2 and P4502E1 for subgroups of Chinese alcoholic patients, defined by diagnoses of AVN (n = 51), acute pancreatitis (n = 92) and liver cirrhosis (n = 159), and for 280 non-alcoholic patients. RESULTS: Analysis revealed that ADH2*1 allele frequency was significantly lower for the alcoholic AVN than for the cirrhosis subgroup. However, no significant difference was found between the alcoholic AVN and pancreatitis subgroups. Furthermore, ALDH2*2 prevalence was not found to differ significantly between the alcoholic subgroups. When compared with our previously published data for alcoholic patients with oesophageal carcinoma, ADH2*1 carriage was significantly less frequent for the alcoholic AVN patients in the current study. Further, ALDH2*2 carriage was significantly less frequent for the alcoholic AVN subgroup than for the oesophageal carcinoma patients. CONCLUSIONS: The allele frequencies for ADH2*1 and ALDH2*2 are different when comparing subpopulations of alcoholics defined by presence of specific alcohol-induced diseases, suggesting that genetic variation in alcohol-metabolizing enzyme genes accounts for, at least in part, the specific types of organ damage observed. We also found the combination of AVN and cirrhosis to be more prevalent than that of AVN and acute pancreatitis. In contrast, the ADH2 and ALDH2 allele frequencies for the AVN subgroup were more similar to those of the acute-pancreatitis than to the cirrhosis subgroup. These data indicate the possibility that other genetic variations may also influence the type of organ-specific complications in Chinese alcoholics.     

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.     

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 acute ethanol drinking on alcohol metabolism in subjects with different ADH and ALDH genotypes

The effect of different amounts of orally ingested ethanol on plasma alcohol dehydrogenase (ADH) and erythrocyte aldehyde dehydrogenase (ALDH), as well as on the blood ethanol and acetaldehyde levels, was examined in healthy nonalcoholic subjects. The genotypes at ADH2 and ALDH2 locus were identified in enzymatically amplified blood DNA by hybridization with allele-specific oligonucleotides. While the Japanese subject was found to be genotypically heterozygous for both ADH2 and ALDH2, the Caucasian subjects were genotypically homozygous normal for these alleles. A faster ethanol elimination associated with a higher blood acetaldehyde level was observed in the Japanese subject as compared to Caucasian subjects. However, no significant change in ADH and ALDH enzyme activities was detected as the result of acute ethanol intake.     

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.     

乙醇和乙醛脱氢酶基因多态与食道癌易感性

目的 研究乙醇脱氢酶2(ADH2)和乙醛脱氧酶2(ALDH2)基因多态与食道癌易感性.方法 对江苏省泰兴市221例食道癌新发病例和191名对照的饮酒习惯等因素进行调查,采用PCR和变性高效液相色谱法(DHPLC)检测ADH2和ALDH2基因型.结果 (1)与携带ALDH2 G/G基因型者相比,携带ALDH2A/A(OR=5.69,95%CI:2.51～12.18)和ALDH2 G/A(OR=1.70,95%CI:1.08～2.68)基因型者患食道癌危险性明显增加,以携带ALDH2A/A的饮酒者最为显著(OR=8.63,95%CI:2.07～35.95).(2)无论是否饮酒,携带不同ADH2基因型者之间患食道癌的风险差异均无统计学意义.(3)携带ALDH2 A/A或G/A基因型者,不论同时携带何种ADH2基因型患食道癌的风险均显著增加,且作用效应为ALDH2 A/A≥G/A.(4)与同时携带ALDH2 G/G和ADH2 A/A的不饮酒者相比,同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G的饮酒者,患食道癌危险性OR值高达8.36(95%CI:2.98～23.46).结论 饮酒及醇醛脱氢酶基因多态与食道癌的联系主要与ALDH2有关;携带ALDH2A/A和G/A者减少酒精消耗量,有助于降低患食道癌危险性.     

AS-PCR在ADH2、ALDH2基因多态型分析中的应用

[目的]为获得更为简便经济同时精确度足够高的酒精脱氢酶2(ADH2)和乙醛脱氢酶2(ALDH2)基因多态型测定的新方法。[方法]建立并优化等位基因特异性PCR(alle lespecific-PCR，AS-PCR)方法，通过与经典HCR-RFIP方法的分型结果相比较考察其可行性。[结果]AS-PCR方法对60例DNA样本的ADH2、ALDH2基因的分型结果与PCR-RFLP法完全一致，且简便快速，成本低，特异性和准确度也足够高。[结论]AS-PCR方法分析ADH2、ALDH2基因多态型优点明显，尤其适于基层以及大规模调查应用。     

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.

     

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.     

Genetic polymorphism of alcohol dehydrogenase 3 in alcohol liver cirrhosis and in alcohol chronic pancreatitis

AIM: To find the ADH3 genotypes in the Polish population likely to be responsible for higher susceptibility to alcohol disease of the liver and chronic alcohol pancreatitis. METHOD: The ADH3 genotype and ADH3*1 and ADH3*2 alleles frequencies were examined in 198 patients. Genotyping of the ADH3 was performed using PCR-restriction fragment length polymorphism methods on a white cell DNA. RESULTS: The genotype ADH3*1/ADH3*1 was found to be significantly more frequent in alcohol abusers compared with non-drinkers. The examinations of the group of alcohol abusers showed that the genotype ADH3*2/ADH3*2 occurred statistically significantly less frequently in patients with chronic pancreatitis than in those without alimentary lesions (healthy drinkers). The alleles ADH3*1 and genotype ADH3*1/ADH3*1 were significantly more frequent in men than in women, whereas alleles ADH3*2 and genotype ADH3*2/ADH3*2 were more common in women. CONCLUSIONS: The genotype ADH3*2/ADH3*2 is likely to be a protective factor for chronic pancreatitis. Variations in ADH3 genotypes may account for some of the differences in prevalence of alcohol dependence between genders in the Polish population.     

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.