ASSOCIATION OF LIVER FLUKE (OPISTHORCHIS-VIVERRINI) INFESTATION WITH INCREASED EXPRESSION OF CYTOCHROME-P450 AND CARCINOGEN METABOLISM IN MALE HAMSTER LIVER

Synergy between exposure to chemical carcinogens (nitrosamines) and in festation with the liver fluke Opisthorchis viverrini has been demonst rated in a hamster model of hepatocarcinogenesis (Flavell et al., Carc inogenesis 4:927-930, 1983; Thamavit et al., Carcinogenesis 8:1351-135 3, 1987). To elucidate the mechanisms of this interaction we tested th e hypothesis that liver parasitism might influence the expression and activity of carcinogen metabolizing enzymes. We found that one, and pe rhaps more, hamster liver cytochrome P450 (CYP) isozymes immunorelated to mouse CYP2A5 contributed up to 50 or 60% of the hepatic aflatoxin B-1 (AFB) and N-nitrosodiethylamine (NDEA) metabolism, respectively. A s inferred from average enzyme activities and from western blot, immun oinhibition, and substrate (coumarin) inhibition analyses, O. viverrin i infestation increased the expression of enzymes detectable by anti-C YP2A5 antibody as well as NDEA metabolism in male but not in female ha msters. Immunohistochemical analysis of CYP2A expression by anti-mouse CYP2A5 antibody demonstrated that the O. viverrini-associated increas e was not uniformly distributed throughout the liver but occurred in h epatocytes immediately adjacent to areas of inflammation. Immunohistoc hemical analysis of AFB-DNA adducts in the livers of O. viverrini-infe sted hamsters treated with AFB showed that the highest levels of adduc ts were found in the regions of liver where hepatocellular expression of enzymes detectable by anti-CYP2A5 antibody is induced. These result s suggest that a high local expression of CYP isozymes in O. viverrini -infested livers could be a contributing risk factor in the developmen t of liver cancers associated with parasitic hepatitis. (C) 1994 Wiley -Liss, Inc.