Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population.

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.     

Gender-specific interactions between alcohol metabolism genes and severity of quantitative alcohol-related-traits in a Tibetan population

Association between genes influencing alcohol metabolism and alcohol use disorders (AUD) has been extensively studied, but the effect of interactions between these genes and AUD have rarely been tested. Our previous case–control study in a Tibetan population noted that the positive association between *c2 allele of cytochrome P4502E1 (CYP2E1) gene and AUD might only exist in males who are homozygotes for *1 alleles of aldehyde dehydrogenase-2 (ALDH2) and alcohol dehydrogenase-1B (ADH1B) genes, but this interaction did not reach statistical significance. Using the same set of data, the present study was aimed at exploring interactions between these genes and quantitative alcohol-related-trait scores (QARTs), and whether these are influenced by gender. The sample included 383 AUD cases with the alcohol use disorders identification test (AUDIT) score ≥10 and 350 normal controls with the AUDIT score ≤5. QARTs were measured using three factors from AUDIT. Possible associations of QARTs with interactions among genotypes of ALDH2*1/*2, ADH1B*1/*2 and CYP2E1*c1/c2* and sex were analyzed in AUD cases and normal controls separately. The subjects with *2 alleles of ALDH2 or/and ADH1B had significantly lower scores of alcohol intake among controls but had significantly higher scores of alcohol related problems among cases. The score of alcohol intake in male cases who are homozygous for ALDH2*1 and ADH1B*1 and with CYP2E1*c2 allele was significantly higher than that of other cases. These findings suggest that interactions between genes influencing alcohol metabolism are influenced by gender and might affect QARTs differently between the milder-/non-drinkers and AUD cases.     

Alcohol and aldehyde dehydrogenase polymorphisms and alcoholism

The alcohol-flush reaction occurs in Asians who inherit the mutantALDH2 ^*2 allele that produces an inactive aldehyde dehydrogenase enzyme. In these individuals, high blood acetaldehyde levels are believed to be the cause of the unpleasant symptoms that follow drinking. We measured the alcohol elimination rates and intensity of flushing in Chinese subjects in whom the alcohol dehydrogenaseADH2 andALDH2 genotypes were determined. We also correlatedADH2, ADH3, andALDH2 genotypes with drinking behavior in 100 Chinese men. We discovered thatADH2 ^*2 andADH3 ^*1, alleles that encode the high activity forms of alcohol dehydrogenase, as well as the mutantALDH2 ^*2 allele were less frequent in alcoholics than in controls. The presence ofALDH2 ^*2 was associated with slower alcohol metabolism and the most intense flushing. In those homozygous forALDH2 ^*1, the presence of twoADH2 ^*2 alleles correlated with slightly faster alcohol metabolism and more intense flushing, although a great deal of variability in the latter was noted.     

Major genetic components underlying alcoholism in Korean population

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

Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men

Among ethanol-metabolizing enzymes, the ALDH2^*2 allele, ADH2^*2 allele, and c2 allele of the cytochrome P450-2E1 (CYP2E1) gene are unique to Orientals. This prompted us to analyze their contribution to drinking behavior in 322 middle-aged Japanese men. The ALDH2^*2 allele, detected in nearly half of the subjects, showed an overwhelming protective effect against a high level of alcohol consumption and problem drinking behavior, as determined by the Kurihama Alcoholism Screening Test (KAST). The ADH2^*2 allele, in 95% of the subjects, exhibited an additive suppressive effect on alcohol consumption, whereas the c2 allele of CYP2E1, in 40% of the subjects, was associated with greater alcohol consumption. Problem drinkers showing a KAST score of 2.0 or higher were frequent among the few subjects with the ADH2^*1/1 genotype, but not in the large number of subjects having the c2 allele of CYP2E1. These findings may explain, at least in part, why in Japan the number of alcoholic patients is small relative to the number of heavy drinkers.     

Genetic polymorphisms of alcohol metabolizing enzymes.

Alcohol metabolism is one of the biological determinants that can significantly influence drinking behavior and the development of alcoholism and alcohol-induced organ damage. Most ethanol elimination occurs by oxidation to acetaldehyde and acetate, catalyzed principally by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Other ethanol oxidation pathways, including catalase and microsomal ethanol-oxidizing system (MEOS/CYP2E1), as well as the nonoxidative pathway (FAEES), which forms fatty acid ethyl esters, appear to play a minor role. The major alcohol metabolizing enzymes exhibit genetic polymorphism and ethnic variation. In this review recent advances in the understanding of the functional polymorphisms of ADH, ALDH and CYP2E1 and their metabolic, physiologic and clinical correlations are presented.     

The role of acetaldehyde in upper digestive tract cancer in alcoholics

Chronic excessive alcohol consumption is the strongest risk factor for upper aerodigestive tract (UADT) cancer. Multiple mechanisms are involved in alcohol-associated cancer development of the UADT, including acetaldehyde (AA) effects. AA is toxic, mutagenic, and carcinogenic. Evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphism or mutation in genes coding for AA generation or detoxification enzymes are associated with increased cancer risk. It has been clearly shown in Asians that individuals carrying the acetaldehyde dehydrogenase 2*2 (ALDH2*2) allele have a significantly increased cancer risk when they consume alcohol. In Caucasians, alcohol dehydrogenase 1*1 (ADH1C*1) allele encodes for an alcohol dehydrogenase (ADH) isoenzyme, which produces 2.5 times more AA than the corresponding allele ADH1C*2. The authors found that the ADH1C*1 allele frequency and rate of homozygosity was significantly associated with an increased risk for alcohol-related cancer. AA seems to be an important factor in alcohol-associated carcinogenesis of the UADT.     

Association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese

The Japanese have a polymorphism in the alcohol dehydrogenase 2 gene (ADH2). The alleles of ADH2 (ADH2*1 and ADH2*2) encode more active and less active forms for ethanol metabolism, respectively. We examined whether liver damage and the insulin–glucose axis vary according to ADH2 genotype in the Japanese. The 2,232 subjects (1,126 men and 1,106 women) were recruited from a population-based prospective cohort study. Clinical evaluations including alcohol consumption, percentage of alcohol drinkers, plasma glucose, HbA1c, insulin, AST, ALT, -GTP, and prevalence of diabetes were compared among the ADH2 genotypes. The percentage of drinkers, alcohol consumption, AST, ALT, and -GTP were higher in group ADH2*1/1 than in group ADH2*1/2 or ADH2*2/2 (all P<0.05). Hence, ADH2*1/1 is associated with excess alcohol intake and liver disorders. However, the prevalence of diabetes did not differ among the three groups. For the glucose–insulin axis, we examined subjects who did not receive insulin therapy or oral anti-diabetes medication. While amounts of alcohol consumed and glucose levels were nearly the same between ADH*1/2 and ADH2*2/2, insulin concentrations were lower in ADH2*2/1 than in ADH2*2/2 (P<0.05 in men). This finding suggests that the ADH2*1 allele is associated with a lower insulin concentration when alcohol intake is light or moderate. It also suggests that the genetic effect of ADH2*1 plays an important role in alcohol drinking behavior and in the occurrence of liver injury, but the effect is so mild that it does not influence the glucose–insulin axis or prevalence of diabetes.     

Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant

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.     

Alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase activity in the sera of patients with esophageal cancer

Various alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) exist in the human esophageal mucosa. In our last experiments we have shown that ADH and ALDH are present also in the esophageal cancer cells. Moreover, the activities of total ADH and class IV isoenzymes were significantly higher in cancer tissue than in healthy mucosa, which suggests that these changes may be reflected by enzyme activity in the serum. Therefore, we measured the activity of total alcohol dehydrogenase, and classes I–IV of this enzyme and aldehyde dehydrogenase in the sera of patients with this cancer. Serum samples were taken for routine biochemical investigation from 67 patients with esophageal cancer before treatment. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes, we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was measured by the photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. A statistically significant increase of class IV alcohol dehydrogenase isoenzymes was found in the sera of cancer patients. The median activity of this class isoenzyme in the total cancer group increased by about 26.5% (7.42 mU/l) in comparison to the control level (5.46 mU/l). The total alcohol dehydrogenase activity was significantly higher (30%) among patients with cancer. The activities of other tested ADH isoenzymes and total ALDH were unchanged. The activity of the class I ADH isoenzyme was significantly higher in the sera of drinkers with esophageal cancer than non-drinking patients. The increased total activity of alcohol dehydrogenase and class IV isoenzyme in the sera of patients with esophageal cancer probably can be caused by release of this isoenzyme from cancer cells or might be stimulated by alcohol drinking.     

Influence of ADH1B polymorphism on alcohol use and its subjective effects in a Jewish population

Class I alcohol dehydrogenases (ADHs) are the principal enzymes responsible for ethanol metabolism in humans. Genetic polymorphism at the ADH1B locus (old nomenclature ADH2) results in isozymes with quite different catalytic properties. The frequency of the ADH1B*2 allele varies among ethnic groups. ADH1B*2 is most often observed in Asian populations, and has been shown to be protective against alcoholism. The Jewish population has a higher frequency of the ADH1B*2 allele and lower rates of alcohol-related problems as compared to other Caucasian populations. Thus, it would be of interest to determine whether the ADH1B*2 allele is associated with alcohol consumption and its subjective effects in this group. Four groups of Jewish subjects (male and female college-age samples, and male and female general samples) were recruited from the same region of the United States. All subjects completed a questionnaire to delineate alcohol consumption and its subjective consequences. Genotype at the ADH1B locus was determined for each participant. ADH1B*2 allele frequencies were similar for the Jewish college-age and general population samples. Men in both the college-age and general population in the ADH1B*2 group reported more unpleasant reactions following alcohol consumption than men in the ADH1B*1 group. Men in the general population in the ADH1B*2 group drank alcohol less frequently than men who were homozygous ADH1B*1; there was a similar trend among the women. The ADH1B polymorphism is associated with unpleasant reactions after alcohol consumption, and frequency of alcohol consumption in these Jewish samples.     

Impact of the alcohol-dehydrogenase (ADH) 1C and ADH1B polymorphisms on drinking behavior in nonalcoholic Japanese

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

Association between alcoholism and the dopamine D4 receptor gene.

A point mutation in the aldehyde dehydrogenase 2 gene (ALDH2(2) allele) is considered to be a genetic deterrent for alcoholism; however, 80 of 655 Japanese alcoholics had the mutant allele. Genotype factors that might increase susceptibility by overriding the deterrent showed a higher frequency of a five repeat allele of the dopamine D4 receptor 48 bp repeat polymorphism in alcoholics with ALDH2(2) than in 100 other alcoholics and 144 controls. Alcoholics with the five repeat allele also abused other drugs more often. These data suggest the involvement of the dopamine system in the development of alcoholism and other addictive behaviour.     

人乙醛脱氢酶2基因*1/*2多态性与酒精性疾病

人乙醛脱氢酶2(ALDH2)是乙醇代谢途径中最重要的酶之一,其编码基因aldh2具有高度的多态性.在亚洲的黄种人群中,aldh2*2是频率最高且最重要的突变型.最近的研究显示,aldh2*2能在一定程度上抑制其携带者对酒精的依赖,并与酗酒导致的酒精性中毒、酒精性肝病、上消化道癌及胃癌等疾病之间存在深刻的联系.     

ADH2 and Alcohol-Related Phenotypes in Ashkenazic Jewish American College Students

A variety of genetically influenced alcohol-related phenotypes relate to risk for alcohol dependence. In Asians, variation in the alcohol dehydrogenase (ADH2) gene relates to alcohol dependence, alcohol consumption, and reported alcohol-related symptoms, even after controlling for variation in the aldehyde dehydrogenase (ALDH2) gene. The association of ADH2 polymorphisms with alcohol-related behavior, however, has not been well characterized in non-Asians. This study evaluated 84 Ashkenazic Jewish American college students to determine the prevalence of the ADH2*2 allele (0.31). Carriers of ADH2*2 reported significantly fewer drinking days per month. ADH2*2, however, was not related to alcohol use disorders, alcohol-induced flushing and associated symptoms, number of binge drinking episodes in the past 90 days, maximum number of drinks ever consumed, or self-reported levels of response to alcohol. Results suggest that Ashkenazic Jewish Americans with ADH2*2 alleles drink less frequently, which might contribute, in part, to the overall lower rates of alcoholism in this population.     

The role of alcohol dehydrogenase genes in head and neck cancers: a systematic review and meta-analysis of ADH1B and ADH1C

Alcohol drinking is a major risk factor for head and neck cancer (HNC). This risk may be modified by alcohol dehydrogenase (ADH) genes, particularly ADH1B and ADH1C, that oxidise ethanol to its carcinogenic metabolite, acetaldehyde. A meta-analysis was conducted to assess the association between ADH1B and ADH1C and HNC risk. Twenty-nine studies from 28 articles identified from a literature search were included. Summary odds ratios (meta-ORs) were generated using random effect models. A reduced risk for HNC was associated with carrying the ADH1B*2 and ADH1C*1 alleles that confer faster metabolism of ethanol to acetaldehyde [meta-OR ADH1B, 0.50; 95% confidence interval (CI): 0.37-0.68, 13 studies; meta-OR ADH1C, 0.87; 95% CI: 0.76-0.99, 22 studies]. ADH1B*2 and ADH1C*1 alleles appear to be protective for HNC, possibly due to: (i) decreasing the opportunity for oral microflora to produce acetaldehyde locally from a prolonged systemic circulation of ethanol, (ii) preventing ethanol from acting as a solvent for other carcinogens, and (iii) decreasing the amount of ethanol a person consumes since a consequent peak in systemic acetaldehyde could cause discomfort. These results underscore the importance of ADH1B and ADH1C in the association between alcohol consumption and the risk for HNC.     

Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with acute and chronic pancreatitis

Objective

Acute and chronic pancreatitis is a major complication of alcohol abuse. The pancreas can metabolize ethanol via oxidative pathway involving the enzymes — alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as well as the nonoxidative pathway. Human pancreas tissue contains various ADH isoenzymes and possesses also ALDH activity. In this paper we have measured the activity of alcohol dehydrogenase isoenzymes, and aldehyde dehydrogenase in the sera of patients with acute and chronic pancreatitis.

Methods

Serum samples were taken for routine biochemical investigation from 46 patients suffering from acute pancreatitis and 32 patients with chronic pancreatitis. Total ADH activity was measured by photometric method with p-nitrosodimethylaniline (NDMA) as a substrate and ALDH activity by the fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I isoenzymes we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was measured by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as a substrate.

Results

A statistically significant increase of class III alcohol dehydrogenase isoenzymes was found in the sera of patients with acute and chronic pancreatitis. The median activity of this class isoenzyme in the patients group increased about 35% in the comparison to the control level. The total alcohol dehydrogenase activity was also significantly higher (23.5%) among patients with pancreatitis than healthy ones. The activities of other tested ADH isoenzymes and total ALDH were unchanged. The activity of the class I ADH isoenzyme was significantly higher in the sera of heavy drinkers with pancreatitis.

Conclusion

We can state that the increase of the activity of class III alcohol dehydrogenase isoenzyme in the sera of pancreatitis patients seems to be caused by the release of this isoenzyme from damaged pancreatic cells.     

乙醇代谢酶基因多态与肿瘤关系研究进展

致癌物代谢酶基因多态是肿瘤遗传易感性的一个重要方面,体内参与惭醇代谢的酶主要有乙醇脱氢酶（ADH）,乙醛脱氢酶（ALDH）和细胞色素P450－2E1（CYP2E1）,它们均存在基因多态现象,有研究表明,乙醇代谢酶基因多态与肝癌,胃癌和食管癌等肿瘤存在关联,但结果不一致。     

Cytochrome P450 2E1 and head and neck cancer: Interaction with genetic and environmental risk factors

The present case‐control study investigates the association of polymorphisms in cytochrome P450 2E1 (CYP2E1), involved in the metabolism of tobacco carcinogens and alcohol, with Head and Neck Squamous Cell Carcinoma (HNSCC). In addition, the interaction of CYP2E1 (CYP2E1*5B and CYP2E1*6) with other genetic factors (null genotype of glutathione‐S‐Transferase M1, GSTM1, X‐Ray Repair Cross Complementing Group I, XRCC1 (Arg194Trp), and environmental risk factors such as alcohol and tobacco in modifying HNSCC risk were investigated. Genotypes were determined by the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay in a total of 350 male cases of HNSCC and an equal number of healthy male controls. Statistical analysis showed a significant increase in HNSCC risk in cases with variant genotypes of CYP2E1*5B (RsaI) (O.R. 3.44; 95% C.I. 1.45–8.14) and CYP2E1*6 (DraI) (O.R. 1.76; 95% C.I. 1.28–2.41). Haplotype analysis revealed that haplotype T‐A was associated with a greater than 10‐fold increase in risk for HNSCC. Our data also revealed a several fold increase in HNSCC risk in cases carrying a combination of variant genotypes of CYP2E1 with the null genotype of GSTM1 or XRCC1 variant genotypes. Alcohol or tobacco use (both smoking and chewing) were also found to interact with variant genotypes of CYP2E1 in significantly enhancing HNSCC risk. This increase in risk associated with an interaction of CYP2E1 genotypes with GSTM1 or XRCC1 or with tobacco and alcohol use demonstrates the importance of gene–gene and gene–environment interactions in the development of HNSCC. Environ. Mol. Mutagen. 2009. © 2009 Wiley‐Liss, Inc.     

Polymorphisms in glutathione S-transferases GSTM1, GSTT1 and GSTP1 and cytochromes P450 CYP2E1 and CYP1A1 and susceptibility to cirrhosis or pancreatitis in alcoholics

Excessive alcohol consumption may cause the development of pathologies in the liver and pancreas and various digestive tract cancers. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1 and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, pesticides, environmental pollutants and alcoholic drinks. Polymorphisms in the genes coding for these enzymes have been associated with susceptibility to different diseases, including ethanol-related diseases. To investigate whether these polymorphisms represent risk-modifying factors for ethanol-related diseases, a study was conducted involving 120 Brazilian alcoholics and 221 controls with similar ethnic backgrounds. The distribution of alcoholics groups was as follows: 65 with liver cirrhosis, 14 with chronic pancreatitis and 41 without cirrhosis or pancreatitis. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of liver cirrhosis and pancreatitis, since we found higher frequencies of the Val/Val genotype in alcoholics with liver cirrhosis (15.4%) and pancreatitis (28.6%) in comparison with alcoholics without disease (7.3%). No differences were found in the prevalences of the GSTM1 and GSTT1 null genotypes between alcoholics and the controls and no association was found between the rare CYP2E1 c2 allele and liver cirrhosis and pancreatitis. However, when the mutant CYP1A1 allele was compared between alcoholics and controls, the m2/m2 genotype was more prevalent in the liver cirrhosis alcoholics (7.7%) than in the controls (1.4%) and this difference was statistically significant (P = 0.03, OR = 5.33). In conclusion, our data indicate an association between occurrence of the Val/Val GSTP1 genotype and chronic pancreatitis and an association between the m2/m2 CYP1A1 genotype and alcoholic liver cirrhosis. This could indicate that persons with these genotypes are genetically more prone to the development of alcoholic pancreatitis and alcoholic cirrhosis, respectively.