Peroxisome proliferator-induced hepatocarcinogenesis: levels of activating and detoxifying enzymes in hepatocellular carcinomas induced by ciprofibrate.
It is generally held that altered areas, neoplastic nodules and hepatocellular carcinomas (HCC) induced by mutagenic chemical carcinogens are resistant to the effects of hepatotoxins. This characteristic is attributed to the marked decrease in activating (phase I) enzymes and a several-fold increase in detoxifying (phase II) enzymes. In previous studies, we have shown that hepatic neoplastic lesions induced by non-mutagenic peroxisome proliferators differed from mutagenic carcinogen-induced lesions by lacking gamma-glutamyl transpeptidase and the placental form of glutathione S-transferase. In this study we have examined ciprofibrate-induced HCC for phase I and phase II enzymes. These tumors showed a marked decrease in cytochrome P-450 (53%), cytochrome b5 (79%) and aryl hydrocarbon hydroxylase (55%) activities compared to normal livers. Interestingly, activities of phase II enzymes in these tumors, such as UDP-glucuronyltransferases and sulfotransferases were decreased or remained the same as in the normal livers. In addition, the activity of epoxide hydrolase was also decreased markedly in all peroxisome proliferator-induced HCC. The decrease in the activity of various enzymes appears not to be due to the direct effect of ciprofibrate, since no inhibitory effect was observed after adding this compound in vitro. These findings further amplify the differences between the hepatic lesions induced by mutagenic hepatocarcinogens and non-mutagenic peroxisome proliferators suggesting a divergence in the mechanism by which peroxisome proliferators induce liver tumors.
D000818:Animals; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D004851:Epoxide Hydrolases / Q000378:metabolism; D058607:Fibric Acids; D014453:Glucuronosyltransferase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D008862:Microsomes, Liver / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344; D013466:Sulfurtransferases / Q000378:metabolism
D003573:Cytochrome b Group; D058607:Fibric Acids; D002995:Clofibric Acid; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D013466:Sulfurtransferases; D004851:Epoxide Hydrolases; C019304:ciprofibrate; D002994:Clofibrate