title: Overexpression of cytochrome P-450 isoforms involved in aflatoxin B1 bioactivation in human liver with cirrhosis and hepatitis.
abstract: Studies were carried out to test the hypothesis that inflammatory liver disease increases the expression of specific cytochrome P-450 isoenzymes involved in aflatoxin B1 (AFB) activation. The immunohistochemical expression and localization of various human cytochrome P-450 isoforms, including CYP2A6, CYP1A2, CYP3A4, and CYP2B1, were examined in normal human liver and liver with hepatitis and cirrhosis. The constitutive expression of CYP3A4 in normal liver showed a characteristic pattern of distribution in centrilobular hepatocytes, whereas CYP1A2, CYP2A6, 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 hepatocytes immediately adjacent to areas of fibrosis and inflammation. CYP3A4 and CYP2B1 were induced to a lesser degree, and expression of CYP1A2 was unaffected. In HBV-infected liver, double immunostaining revealed that overexpression of CYP2A6 occurred in hepatocytes expressing the HBV core antigen. In HCV-infected liver, CYP2A6, CYP3A4, and CYP2B1 were overexpressed in hepatocytes with hemosiderin pigmentation. These results suggest that alterations in phenotypic expression of specific P-450 isoenzymes in hepatocytes associated with hepatic inflammation and cirrhosis might increase susceptibility to AFB genotoxicity.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
authors.forename: G M
authors.initials: GM
authors.lastname: Kirby
authors.forename: G
authors.initials: G
authors.lastname: Batist
authors.forename: L
authors.initials: L
authors.lastname: Alpert
authors.forename: E
authors.initials: E
authors.lastname: Lamoureux
authors.forename: R G
authors.initials: RG
authors.lastname: Cameron
authors.forename: M A
authors.initials: MA
authors.lastname: Alaoui-Jamali
mesh_terms: D000328:Adult; D016604:Aflatoxin B1 / Q000633:toxicity*; D000368:Aged; D006502:Budd-Chiari Syndrome / Q000201:enzymology; D002273:Carcinogens / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005260:Female; D006525:Hepatitis, Viral, Human / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis*; D008099:Liver / Q000201:enzymology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology*; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D014758:Viral Core Proteins / Q000378:metabolism
chemical_list: D002273:Carcinogens; D007527:Isoenzymes; D014758:Viral Core Proteins; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1