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Teschke R. Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects. Biomedicines 2018; 6:E106. [PMID: 30424581 PMCID: PMC6316574 DOI: 10.3390/biomedicines6040106] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/13/2018] [Accepted: 10/20/2018] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone.
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Affiliation(s)
- Rolf Teschke
- Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Leimenstrasse 20, D-63450 Hanau, Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Frankfurt/Main, Germany.
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Zeng T, Guo FF, Zhang CL, Song FY, Zhao XL, Xie KQ. Roles of cytochrome P4502E1 gene polymorphisms and the risks of alcoholic liver disease: a meta-analysis. PLoS One 2013; 8:e54188. [PMID: 23335995 PMCID: PMC3545986 DOI: 10.1371/journal.pone.0054188] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 12/11/2012] [Indexed: 12/20/2022] Open
Abstract
Background Previous studies investigating the association between cytochrome P4502E1 (CYP2E1) polymorphisms and the risk of alcoholic liver diseases (ALD) have yielded conflicting results. Thus, a meta-analysis was performed to clarify the association between CYP2E1 polymorphisms and the risks of ALD. Methods A comprehensive literature search was conducted to identify the relevant studies. The fixed or random effect model was selected based on the heterogeneity test among studies. Publication bias was estimated using Begg’s funnel plots and Egger’s regression test. Results A total of 27 and 9 studies were finally included for the association between the CYP2E1 Pst I/Rsa I or Dra I polymorphisms and the risks of ALD, respectively. Overall, the combined results showed that homozygous genotype c2c2 was significantly associated with increase risk of ALD in worldwide populations (c2c2 vs. c1c1: OR = 3.12, 95%CI 1.91–5.11) when ALD patients were compared with alcoholics without ALD. Significant associations between CYP2E1 Pst I/Rsa I polymorphism and ALD risk were also observed in Asians (c2c2 vs. c1c1: OR = 4.11, 95%CI 2.32–7.29) and in Caucasians (c2c2/c1c2 vs. c1c1: OR = 1.58, 95%CI 1.04–2.42) when ALD patients were compared with alcoholics without ALD. However, subgroup analysis stratified by ALD types showed that CYP2E1 Pst I/Rsa I polymorphism was not significantly associated with the risks of alcoholic cirrhosis (ALC). No significant association was observed between CYP2E1 Dra I polymorphism and ALD risks. Conclusion This meta-analysis suggested that CYP2E1 Pst I/Rsa I polymorphism might be not significantly associated with advanced form of ALD (ALC), but might be significantly associated with other form of ALD such as steatosis, hepatisis, fibrosis. Furthermore, CYP2E1 Dra I polymorphism might be not significantly associated with the ALD risks. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.
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Affiliation(s)
- Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, Shandong Province, Jinan City, People’s Republic of China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital of Shandong University, Shandong Province, Jinan City, People’s Republic of China
| | - Cui-Li Zhang
- Institute of Toxicology, School of Public Health, Shandong University, Shandong Province, Jinan City, People’s Republic of China
| | - Fu-Yong Song
- Institute of Toxicology, School of Public Health, Shandong University, Shandong Province, Jinan City, People’s Republic of China
| | - Xiu-Lan Zhao
- Institute of Toxicology, School of Public Health, Shandong University, Shandong Province, Jinan City, People’s Republic of China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, Shandong Province, Jinan City, People’s Republic of China
- * E-mail:
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Genetic polymorphisms in alcohol metabolizing enzymes as related to sensitivity to alcohol-induced health effects. Environ Health Prev Med 2012; 1:193-200. [PMID: 21432474 DOI: 10.1007/bf02931216] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/1996] [Accepted: 09/09/1996] [Indexed: 10/21/2022] Open
Abstract
Three hundred sixty-seven middle-aged Japanese men were analyzed for genotypes of low K(m) aldehyde dehydrogenase (ALDH2) and cytochrome P450 2E1, and for the association with alcohol-induced health effects. Homozygotes for the normal ALDH2 gene (NN) and for the mutant gene (MM) and heterozygotes (NM) were found in 60, 6 and 33%, and homozygotes for the c1 gene (c1/1) and c2 gene (c2/2) of P450 2E1, and heterozygotes (c1/2) in 55, 5 and 40% of subjects, respectively. Mean alcohol consumption significantly differed in the three ALDH2 genotypes: 297 g per week in NN, 158 g in NM and 18 g in MM. It was not different in the three P450 2E1 genotypes, but tended to increase from cl/1 to c2/2 in the NN subjects while there was an inverse relationship in the subjects having the M gene. No difference in alcohol-induced health effects was observed in ALDH2 genotypes, but c2/2 genotype showed higher blood pressure and serum uric acid than the other P450 2E1 genotypes in the subjects consuming 200 g or more of alcohol per week. These results suggest an interactive effect of ALDH2 and P450 2E1 genes on alcohol consumption and a higher sensitivity to alcohol-induced health effects in c2/2 genotypes, although larger scale studies are required to confirm these findings.
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Guo W, Wang Q, Lanzi G, Luobu O, Ma X, Wang Y, Zhen P, Ji Y, Wei G, Wang Z, Deng W, Zhuoma B, Shi X, Yan C, He C, Liu X, Wu Y, Luo H, Collier DA, Ball D, Li T, Hu X. Interaction among genes influencing ethanol metabolism and sex is association with alcohol use disorders in a Tibet population. Am J Med Genet B Neuropsychiatr Genet 2010; 153B:561-569. [PMID: 19655364 DOI: 10.1002/ajmg.b.31020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Associations between alcohol use disorders and polymorphisms of genes influencing ethanol metabolism have been widely reported, but gene-gene and gene-sex interaction studies have rarely been examined. Using a set of samples collected during an epidemiological study of alcohol use disorders AUDs in a Tibetan population in China, we performed a case-control study to investigate the relationship between the functional polymorphisms of genes influencing ethanol metabolism and AUDs. The sample included 383 individuals with an AUDIT score >or=10 and 350 control subjects with the AUDIT score <or=5. All participants were genotyped for ALDH2*1/*2, ADH1B*1/*2, and CYP2E1*c1/c2*. Data were analyzed employing an integrated strategy using MDR, SPSS, and UNPHASED software. The MDR analysis showed that the four-factor model including ADH1B*1/*2, ALDH2*1/*2, and CYP2E1*c1/*c2 polymorphisms, and sex was the most accurate model associated with AUDs with the highest OR 3.299. It also revealed that CYP2E1 *c1/*c2 polymorphism interacted significantly with sex. Independent analysis confirmed that both ADH2*2 and ALDH2*2 allele were significantly associated with AUDs (OR: 0.441 for ADH2*2 and 0.137 for ALDH2*2). CYP2E1*c2 was positively associated with AUDs only in males homozygotic for ALDH2*1 and ADH1B*1 (OR: 2.585). Cumulative association analysis showed the number of protective alleles and genotypes were negatively associated with AUDs. In conclusion, ALDH2*2 and ADH1B*2 alleles were not only independently associated with AUDs but also demonstrated cumulative dosage effects. However the positive association between CYP2E1*c2 allele and AUDs might only exist in males homozygotic for ALDH2*1 and ADH1B*1.
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Affiliation(s)
- Wanjun Guo
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Qiang Wang
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Gongga Lanzi
- Medical School, University of Tibet, Lasha, Tibet, P.R. China
| | - Ouzhu Luobu
- Medical School, University of Tibet, Lasha, Tibet, P.R. China
| | - Xiaohong Ma
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yingcheng Wang
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Puo Zhen
- Medical School, University of Tibet, Lasha, Tibet, P.R. China
| | - Yulin Ji
- Department of Science and Technology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Geng Wei
- Department of Mental Health, People's Hospital of Tibet Autonomous Region, Lasha, P.R. China
| | - Zheng Wang
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China.,Department of Science and Technology, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Wei Deng
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Basang Zhuoma
- Medical School, University of Tibet, Lasha, Tibet, P.R. China
| | - Xiaoming Shi
- Medical School, University of Tibet, Lasha, Tibet, P.R. China
| | - Chengyin Yan
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Chan He
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Xiehe Liu
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Yuejing Wu
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - Hongrong Luo
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China
| | - David A Collier
- Division of Psychological Medicine, Institute of Psychiatry, King's College, London, UK.,SGDP Centre, Institute of Psychiatry, King's College, London, UK
| | - David Ball
- SGDP Centre, Institute of Psychiatry, King's College, London, UK
| | - Tao Li
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China.,Division of Psychological Medicine, Institute of Psychiatry, King's College, London, UK.,SGDP Centre, Institute of Psychiatry, King's College, London, UK
| | - Xun Hu
- Psychiatric Laboratory, Department of Psychiatry, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China.,Division of Psychological Medicine, Institute of Psychiatry, King's College, London, UK.,SGDP Centre, Institute of Psychiatry, King's College, London, UK
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Montane-Jaime K, Moore S, Shafe S, Joseph R, Crooks H, Carr L, Ehlers CL. ADH1C*2 allele is associated with alcohol dependence and elevated liver enzymes in Trinidad and Tobago. Alcohol 2006; 39:81-6. [PMID: 17134660 DOI: 10.1016/j.alcohol.2006.08.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2006] [Revised: 08/09/2006] [Accepted: 08/09/2006] [Indexed: 12/20/2022]
Abstract
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.
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Affiliation(s)
- Karelia Montane-Jaime
- Department of Pharmacology, University of the West Indies, St Augustine, Trinidad and Tobago
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Montano Loza AJ, Ramirez Iglesias MT, Perez Diaz I, Cruz Castellanos S, Garcia Andrade C, Medina Mora ME, Robles Díaz G, Kershenobich D, Gutierrez Reyes G. Association of alcohol-metabolizing genes with alcoholism in a Mexican Indian (Otomi) population. Alcohol 2006; 39:73-9. [PMID: 17134659 DOI: 10.1016/j.alcohol.2006.07.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2006] [Revised: 07/07/2006] [Accepted: 07/07/2006] [Indexed: 12/11/2022]
Abstract
Association studies provide a powerful approach to link DNA variants and genetic predisposition to complex diseases. In this study, we determined the genotype and allelic frequencies of genes encoding enzymes involved in alcohol metabolism in alcoholic and nonalcoholic subjects of related ethnicity. A total of 118 individuals of Otomi Mexican Indian ancestry were included. Fifty-nine were chronic alcoholics according to WHO criteria and alcohol dependents according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria. They were compared to 59 teetotalers or alcohol consumers of <10 g per day. The restriction fragment length polymorphisms analyzed were ADH1B/MaeIII, ALDH2/MboII, CYP2E1/DraI, CYP2E1/RsaI, and CYP2E1/TaqI. Of the studied polymorphisms, a significant difference between alcoholic and nonalcoholic Otomies was observed only in the CYP2E1/TaqI. The common genotype in alcoholics was A1/A2 (54%), and in nonalcoholics the homozygous A2/A2 (63%) (odds ratio [OR]: 0.28; 95% confidence interval [CI]: 0.13-0.60; P=.002). The frequency of the mutant allele A1 was significantly higher in alcoholics than in nonalcoholics (41 vs. 21%; OR: 2.4; 95% CI: 1.3-4.3; P=.003). This documents the presence of a polymorphism of CYP2E1 that is overexpressed in alcoholic Otomies, in which the variant allele (A1 of CYP2E1/TaqI) is associated with increased susceptibility to alcoholism. The appreciation that this finding may be an additional factor contributing to the high frequency of liver cirrhosis in Otomies requires further investigation.
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Segado Soriano A, Santiago Dorrego C, Bañares Cañizares R, Alvarez Fernández E, Bandrés Moya F, Gómez-Gallego F. [Genetic susceptibility to the development of acute alcoholic hepatitis: role of genetic mutations in dehydrogenase alcohol, aldehyde dehydrogenase and cytochrome P450 2E1]. Rev Clin Esp 2006; 205:528-32. [PMID: 16324524 DOI: 10.1016/s0014-2565(05)72632-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Analyze the frequencies of genetic mutation in alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) and cytochrome P450 2E1 (CYP2E1) and establish their possible association with the development of acute alcoholic hepatitis (AAH). METHODOLOGY Case-control study in a total of 85 Spanish patients. We distinguish three groups (one case group and two control groups) based on hepatic histological lesion and alcohol consumption: controls (group 1: teetotalers; group 2: drinkers without AAH; cases: group 3: drinkers with AAH). Case diagnosis was established based on the presence of polymorphonuclear leukocyte infiltrate in histological study. We analyzed the presence of the genetic mutations R47H and R369C (ADH2), E487K (ALDH2) and mutation Rsa I of CYP2E1 (allele c2) by polymerase chain reaction (PCR) and capillary electrophoresis. RESULTS The allele c2 of CYP2E1 was found in 10%, 16% and 50% of the groups 1, 2 and 3 patients, respectively. Presence of the mutation Rsa I showed influence on the development of AAH (odds ratio [OR]: 3.63; confidence interval (95% [CI]: 0.88-15.02). CONCLUSIONS The data suggest a possible association between the presence of the Rsa I of CYP2E1 and the development of AAH in patients with chronic alcohol consumption.
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Affiliation(s)
- A Segado Soriano
- Servicio de Medicina Interna, Hospital Universitario Gregorio Marañón, Madrid
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Stickel F, Osterreicher CH. The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol 2006; 41:209-24. [PMID: 16492723 DOI: 10.1093/alcalc/agl011] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic alcohol consumption is a major cause of liver cirrhosis which, however, develops in only a minority of heavy drinkers. Evidence from twin studies indicates that genetic factors account for at least 50% of individual susceptibility. The contribution of genetic factors to the development of diseases may be investigated either by means of animal experiments, through linkage studies in families of affected patients, or population based case-control studies. With regard to the latter, single nucleotide polymorphisms of genes involved in the degradation of alcohol, antioxidant defense, necroinflammation, and formation and degradation of extracellular matrix are attractive candidates for studying genotype-phenotype associations. However, many associations in early studies were found to be spurious and could not be confirmed in stringently designed investigations. Therefore, future genotype-phenotype studies in alcoholic liver disease should meet certain requirements in order to avoid pure chance observations due to a lack of power, false functional interpretation, and insufficient statistical evaluation.
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Affiliation(s)
- Felix Stickel
- Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland.
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Zintzaras E, Stefanidis I, Santos M, Vidal F. Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease? Hepatology 2006; 43:352-61. [PMID: 16440362 DOI: 10.1002/hep.21023] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Case-control studies that have investigated the association between alcoholism and alcohol-induced liver damage and the ADH2, ADH3, CYP2E1, and ADLH2 polymorphisms have reported controversial or inconclusive results. Thus, we conducted a meta-analysis of 50 association studies of the above polymorphisms. We explored potential sources of heterogeneity and bias, performed subgroup analyses by racial background and sex, performed sensitivity analyses for studies not in Hardy-Weinberg equilibrium, and performed a subgroup analysis for cases that met strict criteria for alcoholism. The present meta-analysis underscores significant associations of ADH2*1, ADH3*2, and ALDH2*1 alleles and the risk of alcoholism (OR = 1.89 [95% CI 1.56-2.28], 1.32 [95% CI 1.12-1.57], and 4.35 [95% CI 3.04-6.23], respectively). The subsequent subgroup analyses showed association for ADH2*1 and ADH3*2 only in East Asians (OR = 2.23 [95% CI 1.81-2.74] and 1.91 [95% CI 1.45-2.53], respectively) and East Asian males (OR = 2.21 [95% CI 1.57-3.10], 1.69 [95% CI 1.10-2.59], respectively). In East Asian males, the OR for ALDH2*1 was 3.66 (95% CI 1.68-7.96). In Caucasians, sensitivity analysis revealed an association for ADH2*1 in alcoholism (OR = 1.62 [95% CI 1.22-1.89]). When strict criteria were imposed, the pattern of results remained unaltered. For liver disease, there were no significant associations for ADH2*1, ADH3*2, or ALDH2*1 in all subpopulations. The CYP2E1 polymorphism showed no association whatsoever. There is evidence that alleles are mainly dominant. In conclusion, there was heterogeneity between studies in alcoholism for ADH2, ADH3, and ALDH2, and lack of bias in all polymorphisms. The above findings reinforce the need for more rigorous studies, and for regular synthesis of studies' results.
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Affiliation(s)
- Elias Zintzaras
- Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
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Cartmell MT, Schulz HU, O'Reilly DA, Yang BM, Kielstein V, Dunlop SP, Halangk W, Demaine AG, Kingsnorth AN. Cytochrome P450 2E1 high activity polymorphism in alcohol abuse and end-organ disease. World J Gastroenterol 2005; 11:6445-9. [PMID: 16425414 PMCID: PMC4355784 DOI: 10.3748/wjg.v11.i41.6445] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2005] [Revised: 04/01/2005] [Accepted: 04/02/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate a possible role for a recently identified polymorphism in the gene of cytochrome P450 2E1, the presence of which is associated with high activity of the enzyme. METHODS Two hundred and thirty-nine alcohol consumers, ICD 10.1/.2 (ALC), and 208 normal controls were studied. PCR amplification of the CYP2E1 gene region was performed to assess polymorphic variation. Fisher's exact test was used to assess the data. RESULTS Twelve normal controls (5.8%) possessed the insertion. Five ALC (2.1%) had the insertion; of these 2 of 144 with alcohol induced chronic pancreatitis, none of 28 with alcoholic liver disease and 3 of 67 without end-organ disease had the polymorphism. A significantly Lower frequency of subjects possessed the insertion than normal controls [P=0.049 (genotype analysis P=0.03)]. To further assess, if there was a relationship to alcohol problems per se or end-organ disease, we compared patients with alcohol induced end-organ disease vs alcoholic controls without end-organ disease vs normal controls which again showed a significant difference [P=0.045 (genotype analysis, P=0.011)], further sub-group analysis did not identify which group(s) accounted for these differences. CONCLUSION We have shown the frequencies of this high-activity polymorphism in alcohol related patient groups for the first time. The frequency is significantly less in alcoholics than normal controls, as with high activity polymorphisms of alcohol dehydrogenase. The biological significance, and whether the relevance is solely for alcoholism or is there a relationship to end-organ disease, would benefit from the assessment in the populations with a greater frequency of this polymorphism.
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Affiliation(s)
- Mark T Cartmell
- Department of Surgery, Derriford Hospital, and Department of Molecular Medicine, Plymouth Postgraduate Medical School, PL6 8DH, United Kingdom.
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Meiler C, Muhlbauer M, Johann M, Hartmann A, Schnabl B, Wodarz N, Schmitz G, Scholmerich J, Hellerbrand C. Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection. World J Gastroenterol 2005; 11:6031-7. [PMID: 16273620 PMCID: PMC4436730 DOI: 10.3748/wjg.v11.i38.6031] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T (-159) polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease (ALD) and chronic hepatitis C virus (HCV) infection.
METHODS: CD14 genotyping was performed by PCR-RFLP analysis in (a) 121 HCV patients, (b) 62 patients with alcohol-associated cirrhosis (Alc-Ci), (c) 118 individuals with heavy alcohol abuse without evidence of advanced liver damage (Alc-w/o Ci), and (d) 247 healthy controls. Furthermore, serum levels of soluble CD14 (sCD14) and transaminases were determined.
RESULTS: The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls (40.3% vs 23.7% or 24.0%, respectively). In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading.
CONCLUSION: Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.
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Affiliation(s)
- C Meiler
- Department of Internal Medicine I, University of Regensburg, Regensburg D-93042, Germany
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Martins A, Cortez-Pinto H, Machado M, Gonçalves MS, Soren S, Marques-Vidal P, de Moura MC, Camilo ME. Are genetic polymorphisms of tumour necrosis factor alpha, interleukin-10, CD14 endotoxin receptor or manganese superoxide dismutase associated with alcoholic liver disease? Eur J Gastroenterol Hepatol 2005; 17:1099-104. [PMID: 16148556 DOI: 10.1097/00042737-200510000-00014] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Four polymorphisms have been described associated with either increased risk for alcoholic liver disease (ALD) or more serious histological lesions: tumour necrosis factor alpha (TNF-alpha) G(-238)A, interleukin-10 (IL-10) C(-627)A, promoter of CD14 endotoxin receptor gene C(-159)T and manganese superoxide dismutase (MnSOD) C(-1183)T/valine --> alanine. METHODS We sought confirmatory evidence, through individual and simultaneous analysis of the four aforementioned polymorphisms, in 176 heavy drinkers: ALD (n = 100) if histology-compatible or clinical evidence of hepatic decompensation; and no evidence of liver disease (NLD) (n = 76) if normal liver tests on two occasions or normal liver histology (steatosis alone). RESULTS Patients with ALD were older (53+/-10 vs. 48+/-10 years, P<0.05), with a similar sex distribution. TNF-alpha G(-238)A showed no difference in heterozygous GA-genotype prevalence (ALD, 9.0%/NLD, 7.9%). IL-10 C(-627)A showed no difference between groups, either homozygote AA (8.0% vs. 10.5%) or heterozygote CA (34.0% vs. 39.5%). CD14 promoter C(-159)T showed no difference between groups in T-allele frequency, either homozygote TT (27% vs. 21%) or heterozygote CT (49% vs. 50%). Alanine MnSOD allele carriers showed no difference between groups in either the heterozygote (55.0% vs. 49.3%) or homozygote (22% vs. 25%). No difference was observed in the probability of having simultaneously two, three or four of the implicated polymorphisms: respectively, 43%, 33% and 0% in ALD, and 43%, 24% and 5% in NLD (not significant). CONCLUSIONS No association was found between the previously implicated polymorphisms of TNF-alpha, IL-10, CD14 and MnSOD, either individually or simultaneously, and the presence of established ALD.
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Abstract
Most tissues of the body contain enzymes capable of ethanol oxidation or nonoxidative metabolism, but significant activity occurs only in the liver and, to a lesser extent, in the stomach. Hence, medical consequences are predominant in these organs. In the liver, ethanol oxidation generates an excess of reducing equivalents, primarily as NADH, causing hepatotoxicity. An additional system, containing cytochromes P-450 inducible by chronic alcohol feeding, was demonstrated in liver microsomes and found to be a major cause of hepatotoxicity.
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Affiliation(s)
- Charles S Lieber
- Bronx VA Medical Center (151-2), 130 West Kingsbridge Road, Bronx, NY 10468, USA.
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14
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Affiliation(s)
- R Bataller
- Institut de Malalties Digestives. IDIBAPS. Hospital Clínic. Barcelona. España.
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15
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Konishi T, Calvillo M, Leng AS, Feng J, Lee T, Lee H, Smith JL, Sial SH, Berman N, French S, Eysselein V, Lin KM, Wan YJY. The ADH3*2 and CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men. Exp Mol Pathol 2003; 74:183-9. [PMID: 12710951 DOI: 10.1016/s0014-4800(03)00006-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
To identify the association between the polymorphisms of genes encoding alcohol metabolizing enzymes and alcoholism, the alcohol dehydrogenase 2 (ADH2), alcohol dehydrogenase 3 (ADH3), aldehyde dehydrogenase 2 (ALDH2), and cytochrome P450 2E1 (CYP2E1) genes were studied in 101 male Mexican American alcoholics. One hundred and four Mexican American nonalcoholic males served as controls. The allele frequency of ADH2*2 (4.3%) and ALDH2*2 (0%), which are considered as protective alleles against alcohol drinking, is very low in Mexican Americans and no association is found between these alleles and alcohol dependence. A strong association was found between ADH3 genotype and alcoholism; the percentage of subjects who carry the ADH3*2 allele was significantly higher in alcoholics (64.4%) than controls (50%). Association was also found between the CYP2E1 RsaI c2 allele and alcohol dependence; the percentage of subjects who carry the RsaI c2 allele was significantly higher in alcoholics (34.7%) than in nonalcoholics (22.1%). The subjects whose alcohol drinking onset age is younger than 25 have much higher CYP2E1 c2 allele frequency than those whose alcohol drinking onset age is older than 25 (22.1% vs 15.7%). Among 101 alcoholics, only 18 subjects carry neither ADH3*2 nor CYP2E1 c2 alleles. For those subjects who have an ADH*1/*1 background, a strong association is found between CYP2E1 RsaI/DraI genotype and alcoholism; the CYP2E1 RsaI c2 and DraI C allele frequencies are much higher in alcoholics than in nonalcoholics (26.4% vs 9.6% for c2 and 27.8% vs 13.5% for C allele). Taken together, ADH3*2 and CYP2E1 c2/C alleles might independently contribute to the development of alcoholism in Mexican American men.
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Affiliation(s)
- Tamiko Konishi
- Department of Pathology, Harbor-UCLA Research and Education Institute, Torrance, CA 90509, USA
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16
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Bataller R, North KE, Brenner DA. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 2003; 37:493-503. [PMID: 12601343 DOI: 10.1053/jhep.2003.50127] [Citation(s) in RCA: 264] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver fibrosis is a highly dynamic process in which multiple genes interact with environmental factors. Recent human epidemiologic studies have identified possible polymorphisms in a number of candidate genes that influence the progression of liver fibrosis. These genetic factors could explain the broad spectrum of responses to the same etiologic agent found in patients with chronic liver diseases. Polymorphisms in genes encoding immunoregulatory proteins, proinflammatory cytokines, and fibrogenic factors may influence disease progression in patients with alcohol-induced liver disease, primary biliary cirrhosis, or chronic hepatitis C. However, some of the studies have yielded contradictory results. For example, conflicting results have been obtained in studies assessing the role of mutations in the hemochromatosis gene on fibrosis progression in patients with chronic hepatitis C. Large-scale, well-designed studies are required to clarify the actual role of this factor and other genetic variants in liver fibrosis.
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Affiliation(s)
- Ramón Bataller
- Department of Medicine, Biochemistry and Biophysics, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA
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17
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Okamoto K, Murawaki Y, Yuasa And I, Kawasaki H. Effect of ALDH2 and CYP2E1 gene polymorphisms on drinking behavior and alcoholic liver disease in Japanese male workers. Alcohol Clin Exp Res 2001. [PMID: 11410736 DOI: 10.1111/j.1530-0277.2001.tb02412.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIMS We examined the relationships of ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease in Japanese male workers. METHODS Two hundred and eighty-seven Japanese men were selected from one metal company to adjust for similar economic and social backgrounds. Drinking behavior was assessed from a self-assessment questionnaire. Genotypes of ALDH2 and CYP2E1 were analyzed with the polymerase chain reaction-single strand conformation polymorphism and with the polymerase chain reaction-restriction fragment length polymorphism, respectively. RESULTS The frequency of the ALDH2 genotype was 55% for typical homozygotes, 42% for heterozygotes, and 4% for atypical homozygotes. The frequency of the CYP2E1 genotype was 62% for c1 homozygotes, 35% for heterozygotes, and 3% for c2 homozygotes. The ALDH2 genotype closely influenced drinking habits, but not the CYP2E1 genotype. Among habitual drinkers, ALDH2 typical homozygotes consumed significantly larger amounts of ethanol than ALDH2 heterozygotes, whereas CYP2E1 genotypes did not influence daily alcohol consumption. Sixteen men (5.6%) were diagnosed with alcoholic liver disease. In terms of ALDH2 genotypes, 12 cases (7.6%) were typical homozygotes and 4 (3.4%) were heterozygotes, whereas the incidence of alcoholic liver disease was not different between c1/c1 homozygotes and c1/c2 heterozygotes. When the interactive contribution of the ALDH2 and CYP2E1 genotypes on drinking behavior and the incidence of alcoholic liver disease were examined, there were no significant differences in the CYP2E1 genotype among the subjects with the same ALDH2 genotype. CONCLUSION The ALDH2 genotype is strongly associated with individual alcohol drinking behavior and the development of alcoholic liver disease in Japanese male workers, but the CYP2E1 genotype is not.
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Affiliation(s)
- K Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Japan.
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18
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19
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Liu S, Park J, Schantz S, Stern J, Lazarus P. Elucidation of CYP2E1 5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer. Oral Oncol 2001; 37:437-45. [PMID: 11377232 PMCID: PMC3715306 DOI: 10.1016/s1368-8375(00)00099-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The CYP2E1 gene, whose protein product plays an important role in the metabolism of various carcinogens, exhibits two polymorphisms recognized by the restriction enzymes RsaI and PstI in its transcriptional regulatory region that have been previously implicated in cancer susceptibility. In this study, we have examined these polymorphisms to elucidate CYP2E1 allelic haplotype, examining the prevalence of these CYP2E1 alleles in Caucasians and African Americans and their potential role in risk for oral cancer. In addition to the c1 (RsaI[+]/PstI[-]) and c2 (RsaI[-]/PstI[+]) alleles reported in previous studies, we have identified two new alleles, c3 (RsaI[+]/PstI[+]) and c4 (RsaI[-]/PstI[-]). The prevalence of the c2 and c3 alleles differs between racial groups, with African Americans exhibiting a lower prevalence of the c2 allele (0.003) but a higher prevalence of the c3 allele (0.049) than Caucasians (0.031 for c2 and 0.004 for c3). Of the 570 subjects screened in this study, the c4 allele was observed in one subject, a Caucasian case with the (c4/c4) genotype. A significant increase in the CYP2E1 (c1/c1) genotype was observed in oral cancer cases as compared to frequency-matched controls in subjects who smoked < or =24 pack-years (P=0.033). No association was observed between CYP2E1 genotype and risk for oral cancer in the heavy-smoking group (i.e. > 24 pack-years). Similar trends were observed for both Caucasians and African Americans. These data suggest that the c1 allele may contribute to increased risk for oral cancer.
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Affiliation(s)
- S. Liu
- Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
| | - J.Y. Park
- H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA
| | - S.P. Schantz
- Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
| | - J.C. Stern
- Department of Otolaryngology, The New York Eye and Ear Infirmary, New York, NY 10003, USA
| | - P. Lazarus
- H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA
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20
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Abstract
Alcoholic liver disease (ALD) develops as a consequence of priming and sensitizing mechanisms rendered by cross-interactions of primary mechanistic factors and secondary risk factors. This concept, albeit not novel, is becoming widely accepted by the field, and more research is directed toward identifying and characterizing the interfaces of the cross-interactions to help understand individual predisposition to the disease. Another pivotal development is the beginning of cell type-specific research to elucidate specific contributions not only of hepatocytes, but also of hepatic macrophages, liver-associated lymphocytes, sinusoidal endothelial cells, and hepatic stellate cells to sensitizing and priming mechanisms. In particular, the critical role of hepatic macrophages has been highlighted and the priming mechanisms concerning this paracrine effect have been proposed. Glutathione depletion in hepatocyte mitochondria is considered the most important sensitizing mechanism. One of the contributing factors is decreased methionine metabolism. Remaining key questions include how altered methionine metabolism contribute to the pathogenesis of ALD; how cross-talk among nonparenchymal liver cells or between nonparenchymal cells and hepatocytes leads to ALD; how dysfunctional mitochondria determine the type of cell death in ALD; and what secondary factors are critical for the development of advanced ALD such as alcoholic hepatitis and cirrhosis.
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Affiliation(s)
- H Tsukamoto
- USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, USC Research Center for Liver Diseases, Department of Pathology, Keck School of Medicine of USC, Los Angeles, California 90033, USA.
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22
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Bellentani S, Saccoccio G, Masutti F, Giacca M, Miglioli L, Monzoni A, Tiribelli C. Risk factors for alcoholic liver disease. Addict Biol 2000; 5:261-8. [PMID: 20575840 DOI: 10.1111/j.1369-1600.2000.tb00190.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Abstract Alcoholic liver disease (ALD) is still a frequent disorder, even though its incidence appears to be decreasing. In spite of intense investigation, the precise mechanisms leading to ALD are still imprecisely known. This is due in part to the lack of a reliable animal model; in part to the difficulty of obtaining clinical data of adequate sample size and derived from unblased populations and finally from the lack of uniformity of the criteria used to define ALD. This paper will review what is known of the various pieces of this puzzle, with particular emphasis not only on the total amount of alcohol consumed, but also on drinking patterns and type of alcoholic beverage ingested. The other potential factors such as age, gender, genetic background, nutritional status, occupational hazards and viral diseases (especially HCV infection) will be touched upon.
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Affiliation(s)
- S Bellentani
- Fondo per lo Studio delle Malattie del Fegato, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy ICGEB, AREA Ricerca, Padriciano, Trieste, Italy
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23
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Wong NA, Rae F, Simpson KJ, Murray GD, Harrison DJ. Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis. Mol Pathol 2000; 53:88-93. [PMID: 10889908 PMCID: PMC1186911 DOI: 10.1136/mp.53.2.88] [Citation(s) in RCA: 67] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
AIMS To investigate the associations between the Rsa I, Dra I, and Taq I genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease or to hepatocellular carcinoma. METHODS DNA samples isolated from 61 patients with alcoholic liver disease, 46 patients with hepatocellular carcinoma, and 375 healthy controls were subjected to polymerase chain reaction amplification followed by digestion with the endonucleases Rsa I, Dra I, or Taq I. Meta-analysis was performed using data from previous studies of Rsa I polymorphism and the risk of alcoholic liver disease. RESULTS No association was found between any of the three polymorphisms and susceptibility to hepatocellular carcinoma. The distributions of Rsa I and Dra I alleles among the patients with alcoholic liver disease were not significantly different from those among the control group. Meta-analysis of this data and previous data concerning Rsa I polymorphism and alcoholic liver disease risk failed to demonstrate any significant association between the two. However, the alcoholic liver disease group in this study showed a significantly lower frequency of the less common Taq I allele compared with the healthy control group (odds ratio, 0.33; 95% confidence interval, 0.12 to 0.78). CONCLUSIONS Possession of the less common Taq I cytochrome p4502E1 allele is associated with reduced susceptibility to alcoholic liver disease. There is no existing evidence that the Taq I polymorphism is directly associated with altered alcohol metabolism, but it might be in linkage disequilibrium with as yet unidentified protective factors.
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Affiliation(s)
- N A Wong
- Department of Pathology, University of Edinburgh Medical School, Scotland, UK.
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24
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Wan YJ, Poland RE, Lin KM. Genetic polymorphism of CYP2E1, ADH2, and ALDH2 in Mexican-Americans. GENETIC TESTING 1999; 2:79-83. [PMID: 10464602 DOI: 10.1089/gte.1998.2.79] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The major enzymes involved in the metabolism of ethanol are alcohol dehydrogenases (ADH) and aldehyde dehydrogenase (ALDH). Some of the isozymes of ADH are expressed polymorphically. Studies investigating a causal link between ADH expression and alcoholic liver disease (ALD) have so far produced conflicting results. The cytochrome P450 2E1 (CYP2E1) represents a second enzyme that can metabolize ethanol. Although normally a minor route of metabolism, its role in chronic alcoholics may be proportionately greater than in nonalcoholics because CYP2E1 is inducible by ethanol. An Rsa I restriction fragment length polymorphism (RFLP) in the 5'-flanking region of the CYP2E1 gene has been identified. Studies have shown that the mutant allele demonstrates greater transcriptional rate, protein level, and enzyme activity when compared with the wild-type allele. The association between the Rsa I site polymorphism and ALD has been reported. In this report, we examined the genotypes of ADH2(2), ALDH2(2), and CYP2E1 in a group of healthy subjects of Mexican-American descent. The ADH2(2) and ALDH2(2) frequencies are 6% and 0%, respectively, which are similar to those which have been reported for Caucasians. In contrast, the Rsa I allele frequency of the CYP2E1 gene is 16%, which is significantly higher than in Caucasians. The high RsaI allele frequency found in Mexican-Americans suggests that it might play a role in the development of ALD in this rapidly growing minority population where ALD is common.
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Affiliation(s)
- Y J Wan
- Department of Pathology, Harbor-UCLA Medical Center, Torrance 90509, USA
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25
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Lieber CS. Microsomal Ethanol-Oxidizing System (MEOS): The First 30 Years (1968-1998)-A Review. Alcohol Clin Exp Res 1999. [DOI: 10.1111/j.1530-0277.1999.tb04217.x] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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26
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Rodrigo L, Alvarez V, Rodriguez M, Pérez R, Alvarez R, Coto E. N-acetyltransferase-2, glutathione S-transferase M1, alcohol dehydrogenase, and cytochrome P450IIE1 genotypes in alcoholic liver cirrhosis: a case-control study. Scand J Gastroenterol 1999; 34:303-7. [PMID: 10232877 DOI: 10.1080/00365529950173735] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Only a small percentage of long-term alcoholics develop liver cirrhosis. Genetic and non-genetic factors have been implicated in the risk of developing this disease. Among the genetic factors, case-control studies suggest an association with some polymorphisms at the alcohol dehydrogenase and cytochrome P450IIE1 genes. N-Acetyltransferase-2 metabolizes multiple compounds, transforming some of them to organ-toxic compounds and others into non-toxic molecules. Slow- and rapid-acetylator individuals exist in most human populations, and the mutations responsible for the slow-acetylator genotype have been determined. Slow acetylators, who should be at higher risk of developing breast cancer, and fast acetylators, who have an increased risk of developing colon cancer, can be characterized by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) genotyping. GSTM1 is another detoxifying enzyme for which functional interindividual differences, on the basis of gene polymorphisms, have been described. METHODS We conducted a case-control study in which 120 alcoholic cirrhotics, 30 long-term non-cirrhotic alcoholics, and 200 healthy controls were genotyped for polymorphisms (RFLPs) at the ADH2, P450IIE1, and NAT2 genes. PCR, followed by restriction enzyme digestion, was performed. The homozygous deletion of the GSTM1 gene was also PCR-analyzed. Genotype frequencies were statistically compared. RESULTS Frequencies for the ADH2, P450IIE1, and GSTM1 polymorphisms did not differ between patients and controls. Individuals homozygous for the NAT2*5 allele, which is the most frequent slow-acetylator (SA) allele and shows the lowest acetylator activity, were at a significantly decreased frequency among the cirrhotic patients compared with controls (9% versus 16%; P = 0.042). The frequency of this SA genotype was significantly increased (40%) in long-term alcoholics who did not develop cirrhosis (P = 0.0041 compared with controls; P= 0.000017 compared with cirrhotics). CONCLUSIONS According to our results, NAT2 activity may be a factor that determines the risk of developing alcoholic liver cirrhosis, and slow acetylators would be protected.
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Affiliation(s)
- L Rodrigo
- Digestive Unit, Hospital Central de Asturias, Oviedo, Spain
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27
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Wormhoudt LW, Commandeur JN, Vermeulen NP. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999; 29:59-124. [PMID: 10066160 DOI: 10.1080/10408449991349186] [Citation(s) in RCA: 217] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
In this review, an overview is presented of the current knowledge of genetic polymorphisms of four of the most important enzyme families involved in the metabolism of xenobiotics, that is, the N-acetyltransferase (NAT), cytochrome P450 (P450), glutathione-S-transferase (GST), and microsomal epoxide hydrolase (mEH) enzymes. The emphasis is on two main topics, the molecular genetics of the polymorphisms and the consequences for xenobiotic metabolism and toxicity. Studies are described in which wild-type and mutant alleles of biotransformation enzymes have been expressed in heterologous systems to study the molecular genetics and the metabolism and pharmacological or toxicological effects of xenobiotics. Furthermore, studies are described that have investigated the effects of genetic polymorphisms of biotransformation enzymes on the metabolism of drugs in humans and on the metabolism of genotoxic compounds in vivo as well. The effects of the polymorphisms are highly dependent on the enzyme systems involved and the compounds being metabolized. Several polymorphisms are described that also clearly influence the metabolism and effects of drugs and toxic compounds, in vivo in humans. Future perspectives in studies on genetic polymorphisms of biotransformation enzymes are also discussed. It is concluded that genetic polymorphisms of biotransformation enzymes are in a number of cases a major factor involved in the interindividual variability in xenobiotic metabolism and toxicity. This may lead to interindividual variability in efficacy of drugs and disease susceptibility.
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Affiliation(s)
- L W Wormhoudt
- Leiden Amsterdam Center for Drug Research, Vrije Universiteit, Department of Pharmacochemistry, The Netherlands
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28
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McCarver DG, Byun R, Hines RN, Hichme M, Wegenek W. A genetic polymorphism in the regulatory sequences of human CYP2E1: association with increased chlorzoxazone hydroxylation in the presence of obesity and ethanol intake. Toxicol Appl Pharmacol 1998; 152:276-81. [PMID: 9772223 DOI: 10.1006/taap.1998.8532] [Citation(s) in RCA: 103] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
To pursue the hypothesis that differences in the regulatory region of CYP2E1 are partially responsible for the intersubject variation in in vivo CYP2E1 activity, restriction enzyme digestion and Southern blotting of 36 human DNA samples were performed. The fractionated DNA was hybridized with a genomic probe to the upstream region of CYP2E1 from positions -2710 to -580. After digestion with the restriction enzyme XbaI, most subjects (69%) were homozygous for the expected band representing the XbaI fragment from positions -2270 to -408, whereas 31% had an unexpected, slightly larger band. Analyses of Southern blots of the same DNA samples cut by other restriction enzymes were consistent with the larger band containing an estimated 100-bp insertion and localized the mutation to a region from positions -2270 to -1672. To determine the functional significance of this mutation, in vivo CYP2E1 metabolic ability was determined in the same subjects using the 6-hydroxylation of chlorzoxazone as a probe. The presence of the insertion mutation was associated with greater CYP2E1 metabolic ability, but only among individuals who either were obese or had recently consumed ethanol (p < 0.01, both). These data are consistent with a DNA insertion that is associated with altered CYP2E1 induction. The incidence of the mutation was 31% among 65 African Americans and 6.9% among 58 Caucasians (p < 0.01). Thus, this CYP2E1 regulatory polymorphism not only enhances CYP2E1 metabolic ability, but is sufficiently common to impact susceptibility to CYP2E1-related diseases in at least two ethnic groups.
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Affiliation(s)
- D G McCarver
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA
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29
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Parsian A, Cloninger CR, Zhang ZH. Association Studies of Polymorphisms of CYP2E1 Gene in Alcoholics with Cirrhosis, Antisocial Personality, and Normal Controls. Alcohol Clin Exp Res 1998. [DOI: 10.1111/j.1530-0277.1998.tb03884.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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30
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Bassendine MF, Day CP. The inheritance of alcoholic liver disease. BAILLIERE'S CLINICAL GASTROENTEROLOGY 1998; 12:317-35. [PMID: 9890075 DOI: 10.1016/s0950-3528(98)90137-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Available evidence supports the concept that alcoholic liver disease (ALD) is a multifactorial disease with a heritable component. A number of polymorphic genes with small and additive effects will thus encode susceptibilty to this 'polygenic' disease. Molecular genetic studies of ALD are in their infancy, and methods available for the genetic dissection of complex traits are discussed. Some candidate genes have been identified, and studies have been undertaken to test for association between specific alleles and ALD susceptibility. There is evidence to support a role for alleles of two genes encoding enzymes involved in the oxidative metabolism of alcohol (acetaldehyde dehydrogenase2*2 and cytochrome P4502E1 c2 allele) in susceptibility to ALD. More recently, attention has focused on cytokines, and there are now data showing association of specific alleles of both tumour necrosis factor alpha and interleukin-10 with predisposition to ALD. These candidate genes need to be subjected to rigorous evaluation in different populations. Such research should help to define more precisely the molecular mechanisms underlying the development of ALD in a sub-population (< 20%) of alcoholics, thereby improving the hepatologist's ability to develop rational treatments.
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Affiliation(s)
- M F Bassendine
- Centre for Liver Research, Medical School, Newcastle upon Tyne, UK
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31
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Abstract
BACKGROUND/AIMS In addition to the possible toxicological impact of cytochrome P4502E1 (CYP2E1) in alcohol-induced liver damage, its activity can be regarded as a variable for drug action in patients with alcoholic liver disease as CYP2E1 is involved in the metabolism of several drugs, for example, paracetamol and halogenated anesthetics. The purpose of our study was to acquire detailed knowledge of CYP2E1 activity in patients with progressingly severe manifestations of alcoholic liver disease. METHODS The concentration ratio of 6-hydroxy-chlorzoxazone/chlorzoxazone in plasma 2 h after ingestion of 500 mg chlorzoxazone (so-called metabolic ratio) has been shown to reflect CYP2E1 activity in vivo. We examined CYP2E1 activity in 56 Caucasian inpatients with minor (n=20), more pronounced (n=14) and severe alcoholic liver disease (n=22). Alcohol abusers were compared to healthy teetotallers (n=14). RESULTS Metabolic ratios were increased 3-fold in actively drinking (ethanol-induced) compared to abstaining (non-induced) patients with alcoholic liver disease (1.19+/-0.84 vs. 0.44+/-0.45, mean+/-SD, (p<0.0001). CYP2E1 activity was significantly lower in non-induced patients with severe alcoholic liver disease (0.19+/-0.10) than in healthy controls (0.50+/-0.28, p<0.01), abstaining alcohol abusers with minor (0.67+/-0.60, p<0.01) and more pronounced alcoholic liver disease (0.53+/-0.31, p<0.01). When non-induced patients with alcoholic liver disease were arranged in progressing order of liver damage (minor, more pronounced, severe alcoholic liver disease), there was a significant decline in CYP2E1 activity (p=0.0008). CONCLUSIONS In non-induced patients, CYP2E1 activity decreases in line with severity of alcoholic liver disease. CYP2E1-mediated drug metabolism is significantly impaired in severe alcoholic liver disease.
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Affiliation(s)
- K Dilger
- Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany
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Tanaka F, Shiratori Y, Yokosuka O, Imazeki F, Tsukada Y, Omata M. Polymorphism of alcohol-metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men. Alcohol Clin Exp Res 1997. [PMID: 9194910 DOI: 10.1111/j.1530-0277.1997.tb03808.x] [Citation(s) in RCA: 102] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alcohol is known to be mainly metabolized in the liver by alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2), and cytochrome P-450IIEI. The purpose of this study was to clarify the role of polymorphism of these ethanol-metabolizing enzymes in drinking behavior and the progression of alcoholic liver disease among Japanese men. Polymorphism of the ADH2, ALDH2, and P-45IIEI genes were determined by polymerase chain reaction, followed by restriction fragment-length polymorphism analysis in 189 normal Japanese men and 26 male patients with alcoholic liver disease. Drinking behavior was estimated by self-assessment according to DSM-III-R criteria. Facial flushing was reported in 91 subjects heterozygous for ALDH2*1/*2 and in two subjects homozygous for ALDH2*2/*2, but was not found in 96 subjects homozygous for ALDH2*1/*1. In contrast, polymorphism of ADH2 and P-450IIEI did not differ between flushers and nonflushers. Although the flushers only drank a small amount of alcohol (< 20 g of ethanol/day), the nonflushers were divided into a group of moderate drinkers (20 to 80 g/day; n = 54) and a group of heavy drinkers (> 80 g/day; n = 42). A high preponderance of heterozygosity for the ADH2*1/*2 genes (20/42; 60%) and a high frequency of the ADH2*1 allele were found in heavy drinkers, compared with moderate drinkers. However, cytochrome P-45IIEI gene polymorphism was similar among the moderate and heavy drinkers. Not only a high frequency of the ALDH2*1 and ADH2*1 alleles, but also a high frequency of the P-450IIEI c2 allele was found in the patients with alcoholic liver disease. From these results, the drinking behavior of Japanese men is strongly influenced by the ALDH2*1 allele, and the level of alcohol intake is affected by the ADH2*1 allele, but not by cytochrome P-45IIEI. However, progression to alcoholic liver disease among heavy drinkers may be affected by the cytochrome P-450IIEI c2 allele.
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Affiliation(s)
- F Tanaka
- Department of Internal Medicine (II), Faculty of Medicine, University of Tokyo, Japan
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Yamada Y, Ikai E, Honda R, Tsuritani I. Genotype of cytochrome P450 2E1 and alcohol-related blood pressure elevation in Japanese men. Blood Press 1997; 6:112-6. [PMID: 9105651 DOI: 10.3109/08037059709061809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Three-hundred-and-sixty-seven unrelated Japanese male workers aged between 36 and 61 years were analysed for the genotypes of cytochrome P450 2E1 (CYP2E1), and the association with alcohol-related health effects including blood pressure (BP) elevation. Homozygous for the c1 (wild) gene was found in 204 men (55%), homozygous for the c2 (variant) gene in 17 (5%), and heterozygous in 146 (40%). Arithmetic means of alcohol consumed per week in the genotypes of c1/c1, c1/c2 and c2/c2 were 218, 257 and 211 g, respectively, and were not statistically different. BP was elevated with the increase in alcohol consumption, and was significantly higher in the c2/c2 genotype than in the other genotypes among the subjects consuming 200 g or more of alcohol per week. Serum uric acid did not correlate with alcohol consumption in the whole subjects, but it was also higher in drinkers having the c2/c2 genotype. Although the number of subjects was too small for a definite conclusion to be drawn, these results suggest to some extent that Japanese men having the c2/c2 genotype of CYP2E1 are more sensitive to the pressor effect of alcohol. Further studies are required to confirm this.
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Affiliation(s)
- Y Yamada
- Department of Hygiene, Kanazawa Medical University Uchinada, Ishikawa, Japan
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Savolainen VT, Pajarinen J, Perola M, Penttilä A, Karhunen PJ. Polymorphism in the cytochrome P450 2E1 gene and the risk of alcoholic liver disease. J Hepatol 1997; 26:55-61. [PMID: 9148022 DOI: 10.1016/s0168-8278(97)80009-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS To study the genetic susceptibility to alcoholic liver disease, we investigated the association between genetic polymorphism in the cytochrome P450 2E1 gene and the occurrence of alcoholic liver disease. METHODS Four previously described restriction fragment length polymorphisms (RFLPs) in the cytochrome P 450 2E1 gene were analyzed by restriction endonuclease (Dra I, Msp I, Pst I and Rsa I) digestion of polymerase chain reaction amplified DNA segments. Polymorphisms in these loci were compared to the occurrence of fatty liver, alcoholic hepatitis and liver fibrosis in 319 males comprising total abstainers, moderate alcohol consumers and chronic alcoholics. RESULTS The allelic frequencies for each RFLP in this series were: 0.89 and 0.11 (Dra I), 0.98 and 0.02 (Msp I) and 0.99 and 0.01 (Pst I and Rsa I). The distribution of the alleles did not vary significantly between the different consumption groups. The allelic frequencies among patients with fatty liver, alcoholic hepatitis or liver fibrosis were not significantly different from the allelic frequencies among patients with normal liver histology. Comparison of different genotypes among moderate alcohol consumers (n = 43) or chronic alcoholics (n = 243) with or without liver disease showed no statistically significant associations. However, the rare polymorphic (d2) allele in the Dra I RFLP was found slightly more often among moderate consumers as well as alcoholics with alcoholic liver disease. CONCLUSIONS These results indicate that the Msp I, Pst I and Rsa I RFLPs were very rare in the Finnish population, suggesting at most minor contribution to the inherited susceptibility to alcoholic liver disease. Polymorphism in the Dra I locus was more common in this study population, but showed no statistically significant association with alcoholic liver disease.
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Affiliation(s)
- V T Savolainen
- Department of Forensic Medicine, University of Helsinki, Finland.
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Agúndez J, Ladero J, Díaz-Rubio M, Benítez J. Rsa I polymorphism at the cytochrome P4502E1 locus is not related to the risk of alcohol-related severe liver disease. LIVER 1996; 16:380-3. [PMID: 9021717 DOI: 10.1111/j.1600-0676.1996.tb00766.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Ethanol-inducible cytochrome P4502E1 is the main pathway in the non-alcohol dehydrogenase oxidation of ethanol. Its coding gene, CYP2E1, is polymorphic at the Rsa I restriction site in the 5'-flanking region. The mutant genotype c2c2 has a higher transcriptional activity than the genotype c1c1 or c1c2. Heavy drinkers carrying the c2 allele might be at a higher risk of alcoholic cirrhosis since they might synthesize greater amounts of acetaldehyde, the compound believed responsible for hepatotoxicity of ethanol. With the aim of establishing if the c2 allele increases the risk of cirrhosis in heavy drinkers, we studied 58 (6 female) chronic heavy drinkers with liver cirrhosis and 137 healthy normal controls of the same ethnic (white Spaniards) origin. After extraction of DNA from white blood cells, alleles c1 and c2 of CYP2E1 were identified by restriction fragment length polymorphism (RFLP) with endonuclease Rsa I. Fifty-six patients and 130 controls were classified as homozygous c1c1 and two and seven, respectively, as heterozygous c1c2. No homozygous c2c2 were detected. The c2 allele frequencies were 0.017 in patients and 0.026 in controls (non-significant differences). We conclude that the Rsa I RFLP polymorphism is probably not related to the risk of cirrhosis in Spanish heavy drinkers.
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Affiliation(s)
- J Agúndez
- Department of Pharmacology, Medical School, University of Extremadura, Badioz, Spain
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36
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Song BJ. Ethanol-inducible cytochrome P450 (CYP2E1): biochemistry, molecular biology and clinical relevance: 1996 update. Alcohol Clin Exp Res 1996; 20:138A-146A. [PMID: 8947253 DOI: 10.1111/j.1530-0277.1996.tb01764.x] [Citation(s) in RCA: 119] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- B J Song
- Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA
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Pajarinen J, Savolainen V, Perola M, Penttilä A, Karhunen PJ. Polymorphism in the cytochrome P450 2E1 gene and alcohol-induced disorders of human spermatogenesis. INTERNATIONAL JOURNAL OF ANDROLOGY 1996; 19:314-22. [PMID: 8985781 DOI: 10.1111/j.1365-2605.1996.tb00482.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The association between alcohol-induced disorders of human spermatogenesis and four restriction fragment polymorphisms (DraI, MspI, PstI and RsaI) of the cytochrome P450 2E1 gene was investigated in an autopsy study on 254 men. Acquaintances were interviewed and the mean daily alcohol consumption of the subjects was calculated on the basis of the interviews. Spermatogenesis score and testicular morphology were assessed by light-microscopy, and cytochrome 2E1 polymorphic genotypes were determined using the polymerase chain reaction. Of the 204 heavy-drinking men, 42 (20.6%) men had normal spermatogenesis (p < 0.001, compared to moderate drinkers). Partial spermatogenic arrest was observed in 76 (37.3%) men and complete spermatogenic arrest in 79 (38.7%) men (p < 0.001, compared to moderate drinkers), whereas seven men (3.4%) had Sertoli cell only syndrome. The overall allelic frequencies for the common and rare polymorphic alleles were 0.98 and 0.02 (MspI) and 0.99 and 0.01 (PstI and RsaI), respectively. No associations between heterozygosity in the MspI, PstI or RsaI loci, or the allelic frequencies of common and rare alleles, and disorders of spermatogenesis were observed. The allelic frequencies for the common and rare polymorphic alleles in the DraI locus were 0.90 and 0.10, respectively. No significant difference was observed, either among moderate or heavy drinkers, in the frequency of the rare allele between men with disorders of spermatogenesis and those with normal spermatogenesis in the respective group, although men with disorders of spermatogenesis in general had a slightly lower frequency of the rare allele when compared to those with normal spermatogenesis. In conclusion, we were unable to demonstrate a significant association between any polymorphisms in the CYP2E1 gene and disorders of spermatogenesis. RsaI, MspI and PstI polymorphisms were extremely rare in our population and could thus possibly be excluded as reasons for genetic susceptibility to disorders of spermatogenesis in our series.
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Affiliation(s)
- J Pajarinen
- Department of Forensic Medicine, University of Helsinki, Finland
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38
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Lucas D, Ménez C, Floch F, Gourlaouen Y, Sparfel O, Joannet I, Bodénez P, Jezequel J, Gouérou H, Berthou F, Bardou LG, Ménez JF. Cytochromes P4502E1 and P4501A1 genotypes and susceptibility to cirrhosis or upper aerodigestive tract cancer in alcoholic caucasians. Alcohol Clin Exp Res 1996; 20:1033-7. [PMID: 8892524 DOI: 10.1111/j.1530-0277.1996.tb01943.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Genetic polymorphisms of various cytochromes P450 have recently been described and could be implicated in the individual susceptibility of alcoholics to ethanol-related diseases. Rsal and Dral polymorphisms of CYP2E1 and Mspl polymorphism of CYP1A1 were studied in 260 controls and 511 alcoholic patients, without any clinical symptoms (n = 202) or with various ethanol-related diseases (n = 309), such as liver cirrhosis (n = 110), esophageal cancer (n = 62), upper aerodigestive tract cancer (n = 96), and other miscellaneous diseases (n = 41). Frequencies of the mutated alleles were found to be 2.5% (Rsal), 7.9% (Dral), and 8.7% (Mspl) in controls; 4%, 14.1%, and 12% in alcoholics without clinical symptoms; and 3.1%, 12.5%, and 11.2% in alcoholics with ethanol-related diseases. The only significant difference was found in the Dral polymorphism, whose frequency was enhanced in alcoholics with (p < 0.05) or without ethanol-related diseases (p < 0.01) when compared with controls. No differences were found between alcoholics without clinical symptoms and alcoholics with cirrhosis, esophageal cancer, or upper aerodigestive tract cancer. However, in liver cirrhosis and in ethanol-related cancers, the rare Dral-C allele was three times less frequent in patients under the age of 45 than in older patients, suggesting a protective role for this allele. In conclusion, our data indicate that the aforementioned mutations do not play a critical role in the development of cirrhosis, esophageal cancer, or upper aerodigestive tract cancers in Caucasians.
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Affiliation(s)
- D Lucas
- Faculté de Médecine de Brest, Laboratoires de Biochimie-Nutrition, France
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Ladero JM, Agúndez JA, Rodríguez-Lescure A, Diaz-Rubio M, Benítez J. RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma. Gut 1996; 39:330-3. [PMID: 8977352 PMCID: PMC1383320 DOI: 10.1136/gut.39.2.330] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND CYP2E1, the coding gene for the ethanol inducible cytochrome P4502E1, is polymorphic at the RsaI restriction site in the 5' flanking region. The mutant allele c2 has a higher transcriptional activity than the wild-type gene c1. P4502E1 catalyses the activation of several environmental carcinogens at a rate that is increased, if only moderately, by longterm ethanol intake. AIMS To establish the distribution of CYP2E1 RsaI polymorphism in patients with hepatocellular carcinoma and to evaluate its possible role in the multifactorial pathogenesis of this tumour. SUBJECTS 101 (84 males) patients with hepatocellular carcinoma and 178 (128 males) healthy controls of the same ethnic (white) and Spanish origin. METHODS After extraction of DNA from white blood cells, alleles c1 and c2 of CYP2E1 were identified by restriction fragment length polymorphism (RFLP) with endonuclease RsaI. RESULTS Homozygous c1c1: 90 patients and 169 controls; heterozygous c1c2: 11 and 9; homozygous c2c2: none (non-significant difference). C2 allele frequencies: 0.055 in patients, 0.025 in controls (non-significant difference) and 0.108 in the 37 patients who had drunk more than 50 g of ethanol/day (p = 0.0035, odds ratio versus controls: 4.67; 95% confidence limits 1.57 to 13.81). CONCLUSION The carrier state of one copy of the c2 CYP2E1 gene increases the risk of hepatoma in previously regular ethanol users with chronic liver disease.
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Affiliation(s)
- J M Ladero
- Service of Gastroenterology, San Carlos University Hospital, Department of Medicine, Medical School, Universidad Complutense, Madrid, Spain
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Higuchi S, Muramatsu T, Matsushita S, Murayama M, Hayashida M. Polymorphisms of ethanol-oxidizing enzymes in alcoholics with inactive ALDH2. Hum Genet 1996; 97:431-4. [PMID: 8834237 DOI: 10.1007/bf02267061] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Inactive aldehyde dehydrogenase-2 (ALDH2) is a well-known biological deterrent of heavy drinking among Asians, although some individuals who have inactive ALDH2 do become alcoholics. Unknown biological mechanisms facilitating the development of the disease may operate in such a way that these individuals overcome adverse reactions, or they may lower the intensity of the reactions. To examine our hypothesis that ethanol-oxidizing isoenzymes have lower catalytic properties in some persons, we investigated polymorphisms of ethanol-oxidizing enzymes that may alter their catalytic activities, viz., alcohol dehydrogenase-2 (ADH2) and -3 (ADH3), and cytochrome P450 2E1 (CYTP2E1), among 80 Japanese alcoholics with inactive ALDH2, 575 alcoholics with active ALDH2, and 461 controls. Although higher ADH2*1 and ADH3*2 allele frequencies were observed in alcoholics than in controls, there was no significant difference in ADH2 and ADH3 genotypes between alcoholics with inactive ALDH2 and alcoholics with active ALDH2. The genotype distributions of CYTP2E1 did not differ among the three groups, indicating no allelic association of the c1/c2 polymorphism of CYTP2E1 with alcoholism. These results suggest that genetic variations in ethanol-oxidizing activities are involved in the development of the disease, but that these variations are not specific in alcoholics with inactive ALDH2, a group at genetically low risk for alcoholism.
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Affiliation(s)
- S Higuchi
- National Institute on Alcoholism, Kurihama National Hospital, Kanagawa, Japan
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Effects of genetic polymorphisms in alcohol-metabolizing enzymes on alcohol hypersensitivity and alcohol-related health problems in orientals. Environ Health Prev Med 1996; 1:1-8. [DOI: 10.1007/bf02931165] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/1995] [Accepted: 12/11/1995] [Indexed: 10/21/2022] Open
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Carr LG, Yi IS, Li TK, Yin SJ. Cytochrome P4502E1 genotypes, alcoholism, and alcoholic cirrhosis in Han Chinese and Atayal Natives of Taiwan. Alcohol Clin Exp Res 1996; 20:43-6. [PMID: 8651460 DOI: 10.1111/j.1530-0277.1996.tb01041.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Genetic factors may play a role in the development of alcoholic liver disease (ALD). Cytochrome P4502E1 (CYP2E1) catalyzes the oxidation of ethanol, producing acetaldehyde and free radicals capable of reacting with and peroxidizing cell membranes. Polymorphisms have been identified in the 5-flanking region of the CYP2E1 gene that may alter the transcriptional activity. In our laboratory, no difference in c1 and c2 allele frequencies was observed between alcoholic patients with or without liver disease in Caucasian men, but there is reported data to the contrary for other populations. To determine if there is a differential susceptibility to ALD between ethnic groups that differ in the frequency of the c2 allele, we studied 30 Han Chinese with severe alcoholic liver disease. Allele frequencies of alcoholics with cirrhosis were compared with 46 alcoholic and 100 nonalcoholic Han individuals without liver disease. To identify the type A (homozygous for c1), type B (heterozygous for c1 and c2) and type C (homozygous for c2) genotypes, DNA encompassing the polymorphisms was amplified by polymerase chain reaction, slot-blotted, and probed with allele-specific oligonucleotides, No significant differences in c2 allele frequencies were found: 0.23 for alcoholics with severe liver disease, 0.20 for alcoholics without liver disease, and 0.26 for the normal population. There also was no difference in c2 allele frequencies between alcoholic and nonalcoholic Atayal natives from Taiwan. Therefore, our results suggest that the allelic variations at the CYP2E1 gene locus also do not significantly affect the development of alcoholism or ALD in Han Chinese and Atayal natives of Taiwan.
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Affiliation(s)
- L G Carr
- Departments of Medicine, Indiana University School of Medicine, Indianapolis 46202-5121, USA
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43
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Yamauchi M, Maezawa Y, Mizuhara Y, Ohata M, Hirakawa J, Nakajima H, Toda G. Polymorphisms in alcohol metabolizing enzyme genes and alcoholic cirrhosis in Japanese patients: a multivariate analysis. Hepatology 1995. [PMID: 7557863 DOI: 10.1002/hep.1840220419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and P450IIE1 are the primary enzymes that catalyze the conversion of ethanol to acetaldehyde and then to acetate. Genetic polymorphisms have been reported in ADH2, ADH3, ALDH2, and the 5'-flanking region of P450IIEI. In this study, we used multivariate analysis to determine which genetic polymorphisms in alcohol metabolizing enzymes were independently associated with the development of alcoholic cirrhosis. Thirty-four noncirrhotic alcoholic patients, including 27 with fatty liver and 7 with nonspecific changes, and 46 patients with alcoholic liver cirrhosis were studied. Restriction fragment length polymorphisms (RFLPs) in the ADH2 and P450IIE1 genes were detected by digestion of polymerase chain reaction (PCR)-amplified DNA with MaeIII and RsaI, respectively. In the ALDH2 gene, RFLPs were detected by differences in the MboII site after PCR amplification. By multivariate analysis of four significant factors including total alcohol intake, ADH, ALDH, and P450IIE1 using the multiple logistic regression model, genotype ADH2(2)/ADH2(2) (P = .029) and genotype c1/c1 of P450IIE1 (P = .013) were found to be independently associated with alcoholic cirrhosis. The odds ratios for ADH2(2)/ADH2(2) genotype and the type A genotype of P450IIE1 (c1/c1) were 4.600 and 4.006, respectively. These results suggest that ADH2 and P450IIE1 gene polymorphisms may be independently associated with the development of alcoholic liver cirrhosis in Japan.
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Affiliation(s)
- M Yamauchi
- First Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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