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.     

中国五个民族人群样本中酒精代谢相关酶基因多态型分布比较

采用聚合酶链式反应 限制性片段长度多态性 (PCR RFLP)方法测定酒精脱氢酶 2 (ADH2 )和乙醛脱氢酶 2 (ALDH2 )的基因型 ,以获得ADH2、ALDH2基因多态型在中国汉、回、蒙古、维吾尔、白五个民族正常人群样本中的分布并对其进行比较。结果显示 :(1)五民族中均为杂合型ADH2与纯合型ALDH2占优势 ;(2 )ADH2、ALDH2基因型在五民族的分布间存在一定差异     

Individual susceptibility and alcohol effects:biochemical and genetic aspects

The large interethnic and interindividual variability in alcohol-induced toxic effects comes from a combination of genetic and environmental factors, influencing ethanol toxicokinetics. The hepatic enzymatic systems involved in ethanol metabolism are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and microsomal P4502E1 (CYP2E1). ADH oxidizes ethanol to acetaldehyde, which is very efficiently oxidized to acetate by ALDH. About 10% of moderate quantities of ethanol is metabolised by CYP2E1; the percentage increases when ADH is saturated. During ethanol metabolism reactive oxygen species and hydroxyethyl radicals are generated, causing oxidative stress, responsible for most ethanol-induced liver damage. For their critical role in detoxifying radicals, glutathione S-transferase are gaining attention in the etiology of alcoholism. All these enzymes have been shown to be polymorphic, giving rise to altered phenotypes. For this reason recent studies have looked for a correlation between metabolic variability and differences in alcohol abuse-related effects.     

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.     

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。     

ALDH2和CYP2E1基因多态性及饮酒习惯与肝细胞癌易感性的关系

目的研究乙醛脱氢酶2(ALDH2)和细胞色素P4502E1(CYP2E1)基因多态性与饮酒因素交互作用在广西原发性肝细胞癌发生中的作用。方法对广西壮族自治区300例肝细胞癌和292例正常对照进行流行病学调查研究,并用PCR-RFLP方法检测ALDH2和CYP2E1基因型。结果病例和对照组中ALDH2和CYP2E1变异基因型携带者分别占50.3%、48.0%和32.3%、32.9%(P0.05)。饮酒频度每周≥3次(高频饮酒)且携带变异基因ALDH2和CYP2E1者发生肝癌的危险度分别是饮酒频度每周3次(低频饮酒)且携带野生基因型者的3.334倍(95%CI=1.746～6.406)和1.803倍(95%CI=0.974～3.336),同时携带两变异基因型者患肝癌风险为1.200倍(95%CI=0.730～1.972),且饮酒增加两变异基因型携带者的肝癌发病风险(OR=1.816,95%CI=0.985～3.348)。结论单一ALDH2或CYP2E1基因型与肝细胞癌易感性无关;但高频饮酒且携带变异基因ALDH2或CYP2E1者患肝癌风险增加,且两变异基因型单倍体增加肝癌发病风险。提示乙醇在增加肝癌发病风险的过程中存在基因-环境和基因-基因相互作用。     

Polymorphisms for vinyl chloride metabolism in French vinyl chloride workers

Genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) have been shown to influence the degree of genetic damage in Taiwanese workers exposed to the carcinogen - vinyl chloride(VC). Certain French VC workers have been found to express biomarkers of mutant forms of cancer-related proteins (ras-p21 and p53) that have been related to their exposure. ALDH2 and CYP2E1 polymorphisms were investigated in 211 of these workers in an attempt to correlate differences in VC metabolic capacity with differences in the presence of these biomarkers. All of the workers were found to have the normal, wild-type ALDH2 gene, and none of them were found to be homozygous for the variant CYP2E1 allele. Sixteen workers were found to be heterozygous for the variant CYP2E1 allele. After adjusting for age, smoking, drinking and cumulative VC exposure, the odds ratio for the presence of either the mutant ras-p21 or the mutant p53 biomarker in these heterozygous workers was found to be statistically significantly increased in comparison to their homozygous, wild-type counterparts (OR = 5.05; 95% CI = 1.10-23.25). However, as opposed to the case in Taiwanese workers, these polymorphisms are relatively uncommon, and thus differences in ALDH2 and CYP2E1 can account for only a small proportion of the variability in mutagenic response to VC exposure in a Caucasian population.     

ALDH2 promoter polymorphism has no effect on the risk for alcoholism

AIM: To test for the possible association between mitochondrial aldehyde dehydrogenase (ALDH2) promoter polymorphism and alcoholism. METHODS: Genotyping to identify the polymorphisms in 515 alcoholic patients and 361 normal controls was performed. RESULTS: There were no significant differences between the genotype and allele frequencies of the -357A/G polymorphism in alcoholics and normal controls. Linkage disequilibrium was observed between the promoter and exon 12 polymorphisms. CONCLUSION: These results suggest the ALDH2 promoter polymorphism does not affect the risk for alcoholism.     

Sex-specific differences in the association of a common aldehyde dehydrogenase 2 gene polymorphism and alcohol consumption with stroke risk in a Korean population: a prospective cohort study

BACKGROUND/OBJECTIVESIt is well-known that alcohol consumption is associated with stroke risk as well as with aldehyde dehydrogenase 2 gene (ALDH2) polymorphisms. However, it is unclear whether ALDH2 polymorphisms are associated with stroke risk independent of alcohol consumption and whether such association is modified by sex. We evaluated sex-specific associations of a common ALDH2 polymorphism and alcohol consumption with stroke risk in a Korean population.SUBJECTS/METHODSWe conducted a prospective cohort study involving 8,465 men and women, aged 40-69 years and free of stroke between June, 2001 and January, 2003, and followed for the development of stroke. We identified new cases of stroke, which were self-reported or ascertained from vital registration data. Based on genome-wide association data, we selected a single-nucleotide polymorphism (rs2074356), which shows high linkage disequilibrium with the functional polymorphism of ALDH2. We conducted Cox proportional hazards regression analysis considering potential risk factors collected from a baseline questionnaire.RESULTSOver the median follow-up of 8 years, 121 cases of stroke were identified. Carrying the wild-type allele of the ALDH2 polymorphism increased stroke risk among men. The multivariate hazard ratio [95% confidence interval] of stroke was 2.02 [1.03-3.99] for the wild-type allele compared with the mutant alleles, but the association was attenuated after controlling for alcohol consumption. Combinations of the wild-type allele and other risk factors of stroke, such as old age, diabetes mellitus, and habitual snoring, synergistically increased the risk among men. Among women, however, the ALDH2 polymorphism was not associated with stroke risk.CONCLUSIONSThe prospective cohort study showed a significant association between a common ALDH2 polymorphism and stroke risk in Korean men, but not in Korean women, and also demonstrated that men with genetic disadvantages gain more risk when having risk factors of stroke. Thus, these men may need to make more concerted efforts to control modifiable risk factors of stroke.     

Genetic polymorphisms in alcohol-metabolizing enzymes and chronic pancreatitis

AIMS: Alcohol misuse is now regarded as an important risk factor for development of chronic pancreatitis (CP). However, not every alcohol misuser develops CP and it therefore might be suggested that susceptibility could be further influenced by inter-individual variations in the activities of alcohol-metabolizing enzymes. Several genetic polymorphisms that may affect the activities of alcohol-metabolizing enzymes have been described. Therefore we determined whether polymorphisms in the genes for alcohol dehydrogenase 3 (ADH3) or cytochrome p450 2E1 (CYP2E1) predispose to the development of CP. METHODS: DNA samples were obtained from 142 adult CP patients with hereditary (n = 21), alcoholic (n = 82) or idiopathic (n = 39) CP. DNA from 128 healthy controls and from 93 alcoholic controls was analysed for comparison. Patients and controls were all of Caucasian origin. Genetic polymorphisms in ADH3 and CYP2E1 were determined by PCR, followed by restriction-fragment-length-polymorphism analyses in all subjects. RESULTS: The frequencies of ADH3 and CYP2E1 c1c2 genotypes did not differ between CP patients and alcoholic and healthy controls. However, a trend for a higher frequency of the CYP2E1 intron 6 D allele was demonstrated in patients with alcohol-induced CP, compared to that of healthy controls (OR = 3.03, 95%CI = 1.0-9.1) or alcoholic controls (OR = 2.76, 95%CI = 0.9-8.7). CONCLUSIONS: These data suggest that the presence of the CYP2E1 intron 6 DD genotype might confer a higher risk of alcoholic CP.     

海参岩藻聚糖硫酸酯对长期饮酒小鼠肝脏保护作用的研究

目的研究海参岩藻聚糖硫酸酯(SC-FUC)对长期饮酒导致的小鼠肝脏功能损伤的改善作用。方法从海地瓜(Acaudina molpadioides)中制备SC-FUC。将ICR小鼠随机分为4组:正常组、模型组以及SC-FUC低、高剂量组,每组12只。各组小鼠按0.08 ml/g bw灌胃受试物,1h后再灌胃白酒,每天一次,连续8w。实验结束后分别检测血清丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)活性,肝脏乙醇脱氢酶(ADH)、乙醛脱氢酶(ALDH)、谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)活性、丙二醛(MDA)、谷胱甘肽(GSH)含量以及肝脏中CYP2e1mRNA的表达量。结果 SC-FUC能显著降低小鼠血清ALT和AST活力(P<0.05),提高肝脏ADH、ALDH、GSH-Px活力(P<0.05)和GSH含量(P<0.05),降低MDA含量(P<0.05);降低肝脏中CYP2e1mRNA的表达量(P<0.05)。结论 SC-FUC对长期饮酒小鼠肝脏具有显著的保护作用。     

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.     

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.     

Research on alcohol metabolism among Asians and its implications for understanding causes of alcoholism

Research into the causes of alcoholism is a relatively recent scientific endeavor. One area of study which could lead to better understanding of the disease is the possibility of a genetic predisposition to alcoholism. Recent work has demonstrated that people have varying complements of enzymes to metabolize alcohol. Current knowledge is examined about the influence of various ethanol metabolizing enzymes on alcohol consumption by Asians and members of other ethnic groups. The two principal enzymes involved in ethanol oxidative metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ADH is responsible for the metabolism of ethanol to acetaldehyde. ALDH catalyzes the conversion of acetaldehyde to acetate. The different isozymes account for the diversity of alcohol metabolism among individuals. An isozyme of ADH (beta 2 beta 2) is found more frequently in Asians than in whites, and an ALDH isozyme (ALDH2), although present in Asians, often is in an inactive form. The presence of an inactive form of ALDH2 is thought to be responsible for an increase in acetaldehyde levels in the body. Acetaldehyde is considered responsible for the facial flushing reaction often observed among Asians who have consumed alcohol. A dysphoric reaction to alcohol, producing uncomfortable sensations, is believed to be a response to deter further consumption. Although the presence of an inactive ALDH2 isozyme may serve as a deterrent to alcohol consumption, its presence does not fully explain the levels of alcohol consumption by those with the inactive isozyme. Other conditions, such as social pressure, and yet undetermined biological factors, may play a significant role in alcohol consumption.     

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。     

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。     

三羟异黄酮保护急性酒精性肝损伤机制研究

目的探讨大豆三羟异黄酮(Gen)对急性酒精性肝损伤保护效果及与乙醇代谢相关酶活性的影响关系。方法 2 w龄昆明种小白鼠(90只)随机分为空白对照组,模型组,Gen试剂对照组(200 mg/kg bw),Gen试剂预防组(分别有50、100、200 mg/kg bw的低、中、高三种剂量,乙醇灌胃前给药)和Gen试剂治疗组(低、中、高三种剂量,乙醇灌胃后给药)9组;用50%乙醇12 ml/kg bw大剂量灌胃雄性小鼠诱发急性酒精性肝损伤,实验连续10 d后测定小鼠血液和肝脏组织的丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、丙二醛(MDA)、甘油三酯(TG)、谷胱甘肽(GSH)、超氧化物歧化酶(SOD)等生化指标,测定肝脏组织的乙醇脱氢酶(ADH)、乙醛脱氢酶(ALDH)和细胞色素氧化酶系(CYP2E1)的活性。结果模型组小鼠血液与肝脏的ALT、AST水平比较空白对照组和Gen试剂对照组明显升高,差异显著(P<0.05=;Gen预防组与治疗组小鼠血液与肝脏的ALT、AST水平比较模型组显著降低,显示有剂量效应,MDA、TG比较模型组显著降低,GSH、SOD比较模型组显著升高,差异显著(P<0.05);Gen预防组与治疗组小鼠血液与肝脏的ADH、ALDH与模型组比较酶活性显著升高,CYP2E1酶活性显著降低;Gen对照组与空白对照组之间各项检测结果无显著差异。结论 Gen对急性酒精性肝损伤有预防保护效果,有影响乙醇代谢酶活性作用,缓解乙醇代谢产生的氧化应激。