Peroxisome proliferator-induced hepatocarcinogenesis: Levels of activating and detoxifying enzymes in hepatocellular carcinomas induced by ciprofibrate

M. Sambasiva Rao*, Demetri M. Kokkinakis, V. Subbarao, Janardan K. Reddy

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

It is generally held that altered areas, neoplastic nodules and hepatocellular carconimas (HCC) induced by mutagenic chemical carcinogens are resistant to the effects of hepatotox ins. This characteristic is attributed to the marked decrease in activating (phase I) enzymes and a several-fold increase in detoxifing (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 γ-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.

Original languageEnglish (US)
Pages (from-to)19-23
Number of pages5
JournalCarcinogenesis
Volume8
Issue number1
DOIs
StatePublished - Jan 1 1987

ASJC Scopus subject areas

  • Cancer Research

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