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. 1996 Jul;59(1):128–134.

Chronic hepatitis B carriers with null genotypes of glutathione S-transferase M1 and T1 polymorphisms who are exposed to aflatoxin are at increased risk of hepatocellular carcinoma.

C J Chen 1, M W Yu 1, Y F Liaw 1, L W Wang 1, S Chiamprasert 1, F Matin 1, A Hirvonen 1, D A Bell 1, R M Santella 1
PMCID: PMC1915093  PMID: 8659516

Abstract

This study was carried out to elucidate the effect of glutathione S-transferase (GST) Ml and Tl polymorphisms on the aflatoxin-related hepatocarcinogenesis among chronic carriers of hepatitis B surface antigen (HBsAg). A total of 32 newly diagnosed hepatocellular carcinoma (HCC) cases and 73 age-matched controls selected from a cohort of 4,841 chronic HBsAg carriers who had been followed for 5 years were studied. The level of aflatoxin B1 (AFB1)-albumin adducts in their serum samples collected at the recruitment was examined by competitive enzyme-linked immunosorbance assay, and genotypes of GST M1 and T1 were determined by PCR. There was a dose-response relationship between serum level of AFB1-albumin adducts and risk of HCC. The biological gradients between serum AFB1-albumin adducts level and HCC risk were observed among chronic HBsAg carriers who had null genotypes of GST M1 and/or T1 but not among those who had non-null genotypes. The multivariate-adjusted odds ratios of developing HCC for those who had low and high serum levels of AFB1-albumin adducts compared with those who had a undetectable adduct level as the referent (odds ratio = 1.0) were 4.1 and 12.4, respectively, for HBsAg carriers with null GST M1 genotype (P < .01, on the basis of the significance test for trend); 0.7 and 1.4 for those with non-null GST Ml genotype (P = .98); 1.8 and 10.2 for those with null GST T1 genotype (P < .05); and 1.3 and 0.8 for those with non-null GST T1 genotype (P = .93). The interaction between serum AFB1-albumin adduct level and polymorphisms of GST M1 and T1 was at marginal statistical significance levels (.05 < P < .10).

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Selected References

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  1. Allen S. J., Wild C. P., Wheeler J. G., Riley E. M., Montesano R., Bennett S., Whittle H. C., Hall A. J., Greenwood B. M. Aflatoxin exposure, malaria and hepatitis B infection in rural Gambian children. Trans R Soc Trop Med Hyg. 1992 Jul-Aug;86(4):426–430. doi: 10.1016/0035-9203(92)90253-9. [DOI] [PubMed] [Google Scholar]
  2. Beasley R. P. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988 May 15;61(10):1942–1956. doi: 10.1002/1097-0142(19880515)61:10<1942::aid-cncr2820611003>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  3. Bell D. A., Taylor J. A., Paulson D. F., Robertson C. N., Mohler J. L., Lucier G. W. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J Natl Cancer Inst. 1993 Jul 21;85(14):1159–1164. doi: 10.1093/jnci/85.14.1159. [DOI] [PubMed] [Google Scholar]
  4. Bell D. A., Thompson C. L., Taylor J., Miller C. R., Perera F., Hsieh L. L., Lucier G. W. Genetic monitoring of human polymorphic cancer susceptibility genes by polymerase chain reaction: application to glutathione transferase mu. Environ Health Perspect. 1992 Nov;98:113–117. doi: 10.1289/ehp.9298113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chang C. C., Yu M. W., Lu C. F., Yang C. S., Chen C. J. A nested case-control study on association between hepatitis C virus antibodies and primary liver cancer in a cohort of 9,775 men in Taiwan. J Med Virol. 1994 Jul;43(3):276–280. doi: 10.1002/jmv.1890430315. [DOI] [PubMed] [Google Scholar]
  6. Chen C. J., Liang K. Y., Chang A. S., Chang Y. C., Lu S. N., Liaw Y. F., Chang W. Y., Sheen M. C., Lin T. M. Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma. Hepatology. 1991 Mar;13(3):398–406. [PubMed] [Google Scholar]
  7. Chen C. J., Zhang Y. J., Lu S. N., Santella R. M. Aflatoxin B1 DNA adducts in smeared tumor tissue from patients with hepatocellular carcinoma. Hepatology. 1992 Nov;16(5):1150–1155. [PubMed] [Google Scholar]
  8. Eaton D. L., Gallagher E. P. Mechanisms of aflatoxin carcinogenesis. Annu Rev Pharmacol Toxicol. 1994;34:135–172. doi: 10.1146/annurev.pa.34.040194.001031. [DOI] [PubMed] [Google Scholar]
  9. Gallagher E. P., Wienkers L. C., Stapleton P. L., Kunze K. L., Eaton D. L. Role of human microsomal and human complementary DNA-expressed cytochromes P4501A2 and P4503A4 in the bioactivation of aflatoxin B1. Cancer Res. 1994 Jan 1;54(1):101–108. [PubMed] [Google Scholar]
  10. Hatch M. C., Chen C. J., Levin B., Ji B. T., Yang G. Y., Hsu S. W., Wang L. W., Hsieh L. L., Santella R. M. Urinary aflatoxin levels, hepatitis-B virus infection and hepatocellular carcinoma in Taiwan. Int J Cancer. 1993 Jul 30;54(6):931–934. doi: 10.1002/ijc.2910540611. [DOI] [PubMed] [Google Scholar]
  11. Kensler T. W., Egner P. A., Davidson N. E., Roebuck B. D., Pikul A., Groopman J. D. Modulation of aflatoxin metabolism, aflatoxin-N7-guanine formation, and hepatic tumorigenesis in rats fed ethoxyquin: role of induction of glutathione S-transferases. Cancer Res. 1986 Aug;46(8):3924–3931. [PubMed] [Google Scholar]
  12. Lin T. M., Chen C. J., Lu S. N., Chang A. S., Chang Y. C., Hsu S. T., Liu J. Y., Liaw Y. F., Chang W. Y. Hepatitis B virus e antigen and primary hepatocellular carcinoma. Anticancer Res. 1991 Nov-Dec;11(6):2063–2065. [PubMed] [Google Scholar]
  13. Liu Y. H., Taylor J., Linko P., Lucier G. W., Thompson C. L. Glutathione S-transferase mu in human lymphocyte and liver: role in modulating formation of carcinogen-derived DNA adducts. Carcinogenesis. 1991 Dec;12(12):2269–2275. doi: 10.1093/carcin/12.12.2269. [DOI] [PubMed] [Google Scholar]
  14. Peers F. G., Gilman G. A., Linsell C. A. Dietary aflatoxins and human liver cancer. A study in Swaziland. Int J Cancer. 1976 Feb 15;17(2):167–176. doi: 10.1002/ijc.2910170204. [DOI] [PubMed] [Google Scholar]
  15. Peers F. G., Linsell C. A. Dietary aflatoxins and liver cancer--a population based study in Kenya. Br J Cancer. 1973 Jun;27(6):473–484. doi: 10.1038/bjc.1973.60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Peers F., Bosch X., Kaldor J., Linsell A., Pluijmen M. Aflatoxin exposure, hepatitis B virus infection and liver cancer in Swaziland. Int J Cancer. 1987 May 15;39(5):545–553. doi: 10.1002/ijc.2910390502. [DOI] [PubMed] [Google Scholar]
  17. Pemble S., Schroeder K. R., Spencer S. R., Meyer D. J., Hallier E., Bolt H. M., Ketterer B., Taylor J. B. Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism. Biochem J. 1994 May 15;300(Pt 1):271–276. doi: 10.1042/bj3000271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Qian G. S., Ross R. K., Yu M. C., Yuan J. M., Gao Y. T., Henderson B. E., Wogan G. N., Groopman J. D. A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China. Cancer Epidemiol Biomarkers Prev. 1994 Jan-Feb;3(1):3–10. [PubMed] [Google Scholar]
  19. Ross R. K., Yuan J. M., Yu M. C., Wogan G. N., Qian G. S., Tu J. T., Groopman J. D., Gao Y. T., Henderson B. E. Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet. 1992 Apr 18;339(8799):943–946. doi: 10.1016/0140-6736(92)91528-g. [DOI] [PubMed] [Google Scholar]
  20. Sabbioni G., Skipper P. L., Büchi G., Tannenbaum S. R. Isolation and characterization of the major serum albumin adduct formed by aflatoxin B1 in vivo in rats. Carcinogenesis. 1987 Jun;8(6):819–824. doi: 10.1093/carcin/8.6.819. [DOI] [PubMed] [Google Scholar]
  21. Sheabar F. Z., Groopman J. D., Qian G. S., Wogan G. N. Quantitative analysis of aflatoxin-albumin adducts. Carcinogenesis. 1993 Jun;14(6):1203–1208. doi: 10.1093/carcin/14.6.1203. [DOI] [PubMed] [Google Scholar]
  22. Tiollais P., Pourcel C., Dejean A. The hepatitis B virus. Nature. 1985 Oct 10;317(6037):489–495. doi: 10.1038/317489a0. [DOI] [PubMed] [Google Scholar]
  23. Van Rensburg S. J., Cook-Mozaffari P., Van Schalkwyk D. J., Van der Watt J. J., Vincent T. J., Purchase I. F. Hepatocellular carcinoma and dietary aflatoxin in Mozambique and Transkei. Br J Cancer. 1985 May;51(5):713–726. doi: 10.1038/bjc.1985.107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wild C. P., Garner R. C., Montesano R., Tursi F. Aflatoxin B1 binding to plasma albumin and liver DNA upon chronic administration to rats. Carcinogenesis. 1986 Jun;7(6):853–858. doi: 10.1093/carcin/7.6.853. [DOI] [PubMed] [Google Scholar]
  25. Wild C. P., Jiang Y. Z., Allen S. J., Jansen L. A., Hall A. J., Montesano R. Aflatoxin-albumin adducts in human sera from different regions of the world. Carcinogenesis. 1990 Dec;11(12):2271–2274. doi: 10.1093/carcin/11.12.2271. [DOI] [PubMed] [Google Scholar]
  26. Yeh F. S., Yu M. C., Mo C. C., Luo S., Tong M. J., Henderson B. E. Hepatitis B virus, aflatoxins, and hepatocellular carcinoma in southern Guangxi, China. Cancer Res. 1989 May 1;49(9):2506–2509. [PubMed] [Google Scholar]
  27. Yu M. W., Chen C. J. Elevated serum testosterone levels and risk of hepatocellular carcinoma. Cancer Res. 1993 Feb 15;53(4):790–794. [PubMed] [Google Scholar]
  28. Yu M. W., Hsieh H. H., Pan W. H., Yang C. S., CHen C. J. Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma. Cancer Res. 1995 Mar 15;55(6):1301–1305. [PubMed] [Google Scholar]
  29. Yu M. W., You S. L., Chang A. S., Lu S. N., Liaw Y. F., Chen C. J. Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. Cancer Res. 1991 Oct 15;51(20):5621–5625. [PubMed] [Google Scholar]
  30. Zhang Y. J., Chen C. J., Haghighi B., Yang G. Y., Hsieh L. L., Wang L. W., Santella R. M. Quantitation of aflatoxin B1-DNA adducts in woodchuck hepatocytes and rat liver tissue by indirect immunofluorescence analysis. Cancer Res. 1991 Mar 15;51(6):1720–1725. [PubMed] [Google Scholar]
  31. Zhang Y. J., Chen C. J., Lee C. S., Haghighi B., Yang G. Y., Wang L. W., Feitelson M., Santella R. Aflatoxin B1-DNA adducts and hepatitis B virus antigens in hepatocellular carcinoma and non-tumorous liver tissue. Carcinogenesis. 1991 Dec;12(12):2247–2252. doi: 10.1093/carcin/12.12.2247. [DOI] [PubMed] [Google Scholar]
  32. Zhong S., Howie A. F., Ketterer B., Taylor J., Hayes J. D., Beckett G. J., Wathen C. G., Wolf C. R., Spurr N. K. Glutathione S-transferase mu locus: use of genotyping and phenotyping assays to assess association with lung cancer susceptibility. Carcinogenesis. 1991 Sep;12(9):1533–1537. doi: 10.1093/carcin/12.9.1533. [DOI] [PubMed] [Google Scholar]

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