Overexpression of cytochrome P-450 isoforms involved in aflatoxin B1 bioactivation in human liver with cirrhosis and hepatitis.
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.
Kirby
G M
GM
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.
Batist
G
G
Alpert
L
L
Lamoureux
E
E
Cameron
R G
RG
Alaoui-Jamali
M A
MA
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
D002273:Carcinogens; D007527:Isoenzymes; D014758:Viral Core Proteins; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1