OVEREXPRESSION OF CYTOCHROME-P-450 ISOFORMS INVOLVED IN AFLATOXIN B-1BIOACTIVATION IN HUMAN LIVER WITH CIRRHOSIS AND HEPATITIS

Studies were carried out to test the hypothesis that inflammatory live r disease increases the expression of specific cytochrome P-450 isoenz ymes involved in aflatoxin B-1 (AFB) activation. The immunohistochemic al expression and localization of various human cytochrome P-450 isofo rms, including CYP2A6, CYP1A2, CYP3A4, and CYP2B1, were examined in no rmal human liver and liver with hepatitis and cirrhosis. The constitut ive expression of CYP3A4 in normal liver showed a characteristic patte rn of distribution in centrilobular hepatocytes, whereas CYP1A2, CYP2A 6, and CYP2B1 were expressed uniformly throughout the liver acinus. In sections of liver infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the expression of CYP2A6 was markedly increased in hepa tocytes immediately adjacent to areas of fibrosis and inflammation. CY P3A4 and CYP2B 1 were induced to a lesser degree, and expression of CY P1A2 was unaffected. In HBV-infected liver, double immunostaining reve aled that overexpression of CYP2A6 occurred in hepatocytes expressing the HBV core antigen. In HCV-infected liver, CYP2A6, CYP3A4, and CYP2B 1 were overexpressed in hepatocytes with hemosiderin pigmentation. Th ese results suggest that alterations in phenotypic expression of speci fic P-450 isoenzymes in hepatocytes associated with hepatic inflammati on and cirrhosis might increase susceptibility to AFB genotoxicity.