INDUCTION OF SPECIFIC CYTOCHROME P450S INVOLVED IN AFLATOXIN B-1 METABOLISM IN HEPATITIS-B VIRUS TRANSGENIC MICE

The relative roles of hepatitis B virus (HBV) and aflatoxin and their possible mechanism of interaction in the etiopathogenesis of hepatocel lular carcinoma (HCC) are not understood. One hypothesis is that viral infection and associated liver injury alter expression of carcinogen- metabolizing enzymes. We tested this hypothesis in an HBV-transgenic m ouse model in which a synergistic interaction occurs between aflatoxin B-1 (AFB(1)) and HBV in the induction of HCC (Sell et al., Cancer Res 51:1278-1285, 1991). In this transgenic mouse lineage, overproduction of the HBV large envelope protein results in progressive liver cell i njury, inflammation, and regenerative hyperplasia. Initially, two cyto chrome P450s of importance in AFB(1) metabolism in the mice were ident ified, namely Cyp2a-5 and Cyp3a, using specific antibodies and chemica l inhibitors. The expression of these P450 isoenzymes and an alpha-cla ss glutathione S-transferase (GST) isoenzyme, YaYa, were examined. Inc reased expression and altered distribution of Cyp2a-5 were demonstrate d, by immunohistochemical analysis, to be associated with the developm ent of liver injury in mice and to increase with age between 1 and 12 months. Cyp3a expression was also increased in HBV-transgenic mice, bu t the increase was not as clearly related to age. GST YaYa levels were the same in HBV-transgenic mice and their nontransgenic littermates o f all ages. These results show that expression of specific cytochrome P450s is altered in association with overexpression of HBV large envel ope protein and liver injury in this model. This may have general rele vance to human HCC, the etiology of which is associated with a diverse range of liver-damaging agents. (C) 1994 Wiley-Liss, Inc.