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http://dx.doi.org/10.5808/GI.2009.7.4.187

Identification of Polymorphisms in CYP2E1 Gene and Association Analysis among Chronic HBV Patients  

Chun, Ji-Yong (Department of Life Science, Sogang University)
Park, Byung-Lae (Department of Genetic Epidemiology, SNP Genetics, Inc.)
Cheong, Hyun-Sub (Department of Genetic Epidemiology, SNP Genetics, Inc.)
Kim, Jason-Y. (Department of Life Science, Sogang University)
Park, Tae-Joon (Department of Life Science, Sogang University)
Lee, Jin-Sol (Department of Life Science, Sogang University)
Lee, Hyo-Suk (Department of Internal Medicine and Liver Research Institute, Seoul National University)
Kim, Yoon-Jun (Department of Internal Medicine and Liver Research Institute, Seoul National University)
Shin, Hyoung-Doo (Department of Life Science, Sogang University)
Publication Information
Genomics & Informatics / v.7, no.4, 2009 , pp. 187-194 More about this Journal
Abstract
Cytochrome P450 2E1 (CYP2E1) is a member of the cytochrome P450 superfamily, and it is a key enzyme responsible for the metabolic activation of many smallmolecular-weight compounds such as alcohol, which is classified as a human carcinogen. In this study, we identified 19 single nucleotide polymorphisms (SNPs) in CYP2E1 in Korean population. In these SNPs, we examined possible genetic association of CYP2E1 polymorphisms with HBV clearance and the risk of hepatocellular carcinoma (HCC). Five common polymorphic sites were selected, CYP2E1 polymorphisms at rs381-3867, rs3813870, rs2070673, rs2515641 and rs2480257, considering their allele frequencies, haplotype-tagging status and LDs for genotyping in larger-scale subjects (n=1,092). Statistical analysis demonstrated that CYP2E1 polymorphisms and haplotypes show no significant association with HBV clearance, HCC occurrence and onset age of HCC (p>0.05). Previous studies, however, have shown contradictory findings on associations of CYP2E1 polymorphisms with CYP2E1 activities and HCC risk. Comparing the contrasting results of previous researches suggest that CYP2E1 polymorphism is associated with CYP2E1 activity induced by ethanol, but is not directly associated with HCC risk. CYP2E1 variation/haploype information identified in this study will provide valuable information for future studies on CYP2E1.
Keywords
cytochrome P450 2E1 (CYP2E1); hepatocellular carcinoma (HCC); hepatitis B virus (HBV); chronic hepatitis (CH); liver cirrhosis (LC); polymorphism;
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1 Baan, R., Straif, K., Grosse, Y., Secretan, B., El Ghissassi, F., Bouvard, V., Altieri, A., and Cogliano, V. (2007). Carcinogenicity of alcoholic beverages. Lancet Oncol . 8, 292-293   DOI   ScienceOn
2 Bae, S.H., Yoon, S.K., Jang, J.W., Kim, C.W., Nam, S.W., Choi, J.Y., Kim, B.S., Park, Y.M., Suzuki, S., Sugauchi, F., and Mizokami, M. (2005). Hepatitis B virus genotype C prevails among chronic carriers of the virus in Korea. J. Korean Med. Sci . 20, 816-820   DOI   ScienceOn
3 Bosch, F.X., Ribes, J., Cl\acute{e}ries, R., and Dí\acute{a}z, M. (2005). Epidemiology of hepatocellular carcinoma. Clin. Liver Dis. 9, 191-211   DOI   ScienceOn
4 Bruix, J., Sherman, M., Llovet, J.M., Beaugrand, M., Lencioni, R., Burroughs, A.K., Christensen, E., Pagliaro, L., Colombo, M., and Rodes, J. (2001). Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J. Hepatol . 35, 421-430   DOI   ScienceOn
5 Carriere, V., Berthou, F., Baird, S., Belloc, C., Beaune, P., and de Waziers, I. (1996). Human cytochrome P450 2E1 (CYP2E1): from genotype to phenotype. Pharmacogenetics 6, 203-211   DOI   ScienceOn
6 Cruz, A.C., Frentzen, B.H., and Behnke, M. (1987). Hepatitis B: a case for prenatal screening of all patients. Am. J. Obstet. Gynecol . 156, 1180-1183   DOI
7 Gebhardt, A.C., Lucas, D., Menez, J.F., and Seitz, H.K. (1997). Chlormethiazole inhibition of cytochrome P450 2E1 as assessed by chlorzoxazone hydroxylation in humans. Hepatology 26, 957-961   DOI   ScienceOn
8 Girre, C., Lucas, D., Hispard, E., Menez, C., Dally, S., and Menez, J.F. (1994). Assessment of cytochrome P4502E1 induction in alcoholic patients by chlorzoxazone pharmacokinetics. Biochem. Pharmacol. 47, 1503-1508   DOI   ScienceOn
9 Koop, D.R. (1992). Oxidative and reductive metabolism by cytochrome P450 2E1. Faseb. J . 6, 724-730
10 Menashe, I., Rosenberg, P.S., and Chen, B.E. (2008). PGA: power calculator for case-control genetic association analyses. BMC Genet 9, 36   DOI   PUBMED   ScienceOn
11 Odgerel, Z., Nho, K.B., Moon, J.Y., Kee, S.H., Park, K.S., Song, K.J., Baek, L.J., Yeon, J.E., Byun, K.S., Lee, C.H., and Song, J.W. (2003). Complete genome sequence and phylogenetic analysis of hepatitis B virus (HBV) isolates from patients with chronic HBV infection in Korea. J. Med. Virol . 71, 499-503   DOI   ScienceOn
12 Reicks, M.M., and Crankshaw, D.L. (1996). Modulation of rat hepatic cytochrome P-450 activity by garlic organosulfur compounds. Nutr. Cancer 25, 241-248   DOI   ScienceOn
13 Seitz, H.K., and Stickel, F. (2007). Molecular mechanisms of alcohol-mediated carcinogenesis. Nat. Rev. Cancer 7, 599-612   DOI   ScienceOn
14 Yang, C.S., Smith, T.J., and Hong, J.Y. (1994). Cytochrome P-450 enzymes as targets for chemoprevention against chemical carcinogenesis and toxicity: opportunities and limitations. Cancer Res . 54, 1982s-1986s   PUBMED
15 Stickel, F., and Osterreicher, C.H. (2006). The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol 41, 209-224   DOI   ScienceOn
16 Stickel, F., Schuppan, D., Hahn, E.G., and Seitz, H.K. (2002). Cocarcinogenic effects of alcohol in hepatocarcinogenesis. Gut 51, 132-139   DOI   ScienceOn
17 Yoo, B.C., Park, J.W., Kim, H.J., Lee, D.H., Cha, Y.J., and Park, S.M. (2003). Precore and core promoter mutations of hepatitis B virus and hepatitis B e antigen-negative chronic hepatitis B in Korea. J. Hepatol . 38, 98-103   PUBMED
18 Kharasch, E.D., Thummel, K.E., Mhyre, J., and Lillibridge, J.H. (1993). Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1. Clin. Pharmacol. Ther . 53, 643-650   DOI
19 Lee, M.S., Kim, D.H., Kim, H., Lee, H.S., Kim, C.Y., Park, T.S., Yoo, K.Y., Park, B.J., and Ahn, Y.O. (1998). Hepatitis B vaccination and reduced risk of primary liver cancer among male adults: a cohort study in Korea. Int. J. Epidemiol . 27, 316-319   DOI   ScienceOn
20 McCarver, D.G., Byun, R., Hines, R.N., Hichme, M., and Wegenek, W. (1998). 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 . 152, 276-281   DOI   ScienceOn
21 O'Shea, D., Davis, S.N., Kim, R.B., and Wilkinson, G.R. (1994). Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity. Clin. Pharmacol. Ther. 56: 359-367   DOI
22 Song, B.C., Kim, H., Kim, S.H., Cha, C.Y., Kook, Y.H., and Kim, B.J. (2005b). Comparison of full length sequences of hepatitis B virus isolates in hepatocellular carcinoma patients and asymptomatic carriers of Korea. J. Med. Virol. 75, 13-19   DOI   ScienceOn
23 Hayashi, S., Watanabe, J., and Kawajiri, K. (1991). Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene. J. Biochem . 110, 559-565
24 Tanaka, F., Shiratori, Y., Yokosuka, O., Imazeki, F., Tsukada, Y., and Omata, M. (1997). Polymorphism of alcohol-metabolizing genes affects drinking behavior and alcoholic liver disease in Japanese men. Alcohol Clin. Exp. Res . 21, 596-601   DOI   ScienceOn
25 Leclercq, I., Desager, J.P., and Horsmans, Y. (1998). Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress. Clin. Pharmacol. Ther . 64, 144-149   DOI   ScienceOn
26 Yu, M.W., Gladek-Yarborough, A., Chiamprasert, S., Santella, R.M., Liaw, Y.F., and Chen, C.J. (1995). Cytochrome P450 2E1 and glutathione S-transferase M1 polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology 109, 1266-1273   DOI   ScienceOn
27 Watanabe, J., Hayashi, S., and Kawajiri, K. (1994). Different regulation and expression of the human CYP2E1 gene due to the RsaI polymorphism in the 5'-flanking region. J. Biochem . 116, 321-326   DOI
28 Livak, K.J. (1999). Allelic discrimination using fluorogenic probes and the 5' nuclease assay. Genet. Anal . 14, 143-149   DOI   PUBMED   ScienceOn
29 Song, B.C., Cui, X.J., and Kim, H. (2005a). Hepatitis B virus genotypes in Korea: an endemic area of hepatitis B virus infection. Intervirology 48, 133-137   DOI   ScienceOn
30 Grove, J., Brown, A.S., Daly, A.K., Bassendine, M.F., James, O.F., and Day, C.P. (1998). The RsaI polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: effect on age of presentation and dependence on alcohol dehydrogenase genotype. Pharmacogenetics 8, 335-342   DOI   ScienceOn
31 Takahashi, T., Lasker, J.M., Rosman, A.S., and Lieber, C.S. (1993). Induction of cytochrome P-4502E1 in the human liver by ethanol is caused by a corresponding increase in encoding messenger RNA. Hepatology 17, 236-245   DOI   PUBMED
32 Morgan, T.R., Mandayam, S., and Jamal, M.M. (2004). Alcohol and hepatocellular carcinoma. Gastroenterology 127, S87-96   DOI   ScienceOn
33 Tsutsumi, M., Takada, A., and Wang, J.S. (1994). Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. Gastroenterology 107, 1430-1435   DOI   PUBMED
34 Lavanchy, D. (2005). Worldwide epidemiology of HBV infection, disease burden, and vaccine prevention. J. Clin. Virol. 34, S1-3
35 Powell, H., Kitteringham, N.R., Pirmohamed, M., Smith, D.A., and Park, B.K. (1998). Expression of cytochrome P4502E1 in human liver: assessment by mRNA, genotype and phenotype. Pharmacogenetics 8, 411-421   DOI   ScienceOn
36 Inoue, K., Yamazaki, H., and Shimada, T. (2000). Characterization of liver microsomal 7-ethoxycoumarin O-deethylation and chlorzoxazone 6-hydroxylation activities in Japanese and Caucasian subjects genotyped for CYP2E1 gene. Arch. Toxicol. 74, 372-378   DOI   ScienceOn
37 Dilger, K., Metzler, J., Bode, J.C., and Klotz, U. (1997). CYP2E1 activity in patients with alcoholic liver disease. J. Hepatol . 27, 1009-1014   DOI   ScienceOn
38 Barrett, J.C., Fry, B., Maller, J., and Daly, M.J. (2005). Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263-265   DOI   ScienceOn
39 Guengerich, F.P., Kim, D.H., and Iwasaki, M. (1991). Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem. Res. Toxicol. 4, 168-179   DOI   ScienceOn
40 Stephens, M., Smith, N.J., and Donnelly, P. (2001). A new statistical method for haplotype reconstruction from population data. Am. J. Hum. Genet . 68, 978-989   DOI   ScienceOn
41 Ladero, J.M., Agundez, J.A., Rodriguez-Lescure, A., Diaz Rubio, M., and Benitez, J. (1996). RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma. Gut 39, 330-333   DOI   ScienceOn
42 Piao, Y.F., Li, J.T., and Shi, Y. (2003). Relationship between genetic polymorphism of cytochrome P450IIE1 and fatty liver. World J. Gastroenterol . 9, 2612-2615   DOI
43 Lucas, D., Menez, C., Girre, C., Berthou, F., Bodenez, P., Joannet, I., Hispard, E., Bardou, L.G., and Menez, J.F. (1995). Cytochrome P450 2E1 genotype and chlorzoxazone metabolism in healthy and alcoholic Caucasian subjects. Pharmacogenetics 5, 298-304   DOI   ScienceOn
44 Peters, T.J., and Ward, R.J. (1988). Role of acetaldehyde in the pathogenesis of alcoholic liver disease. Mol. Aspects Med . 10, 179-190   DOI   ScienceOn
45 Hedrick, P., and Kumar, S. (2001). Mutation and linkage disequilibrium in human mtDNA. Eur. J. Hum. Genet . 9, 969-972   DOI
46 Marchand, L.L., Wilkinson, G.R., and Wilkens, L.R. (1999). Genetic and dietary predictors of CYP2E1 activity: a phenotyping study in Hawaii Japanese using chlorzoxazone. Cancer Epidemiol. Biomarkers Prev . 8, 495-500
47 El-Serag, H.B., and Mason, A.C. (2000). Risk factors for the rising rates of primary liver cancer in the United States. Arch. Intern. Med. 160, 3227-3230   DOI   ScienceOn