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

Abstract

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.

High Frequency of β-Catenin Mutations in Mouse Hepatocellular Carcinomas Induced by a Nongenotoxic Constitutive Androstane Receptor Agonist

“…Previous work has shown that gene expression patterns of mouse HCCs generated by the genotoxic carcinogen DENA are quite similar to human HCCs with the poorer survival, 45 whereas those of HCCs from mice treated with the nongenotoxic ciprofibrate, a potent peroxisome proliferator and a peroxisome proliferator-activated receptor a ligand, 46 were not. To explore whether a similar difference in the pattern of gene expression could take place in HCCs induced by genotoxic versus nongenotoxic conditions, hierarchical clustering analysis of gene expression patterns was applied to assess the relative similarities between HCCs generated by DENA þ TCP and those induced by TCP alone.…”

Cellular Origin of Cancer: Dedifferentiation or Stem Cell Maturation Arrest?

“…longed administration, enzyme-altered foci appear (70) that are different from those induced by genotoxic chemicals that they do not contain increased carcino-gen-detoxifying enzymes (71,72). Later, AFP-negative cancers are seen (69).…”

Role of hepatitis B virus X repression of C/EBPβ activity in the down-regulation of glutathioneS-transferase A2 gene: implications in other phase II detoxifying enzyme expression

“…Comprehensive mechanistic studies indicate that the induction of phase II enzymes mediate not only cell detoxi cation and survival, but also cancer prevention (Bolton et al 1993;Kensler 1997;Kwak et al 2001). Moreover, it has been shown that alterations in phase II enzyme expression are associated with malignancy and cell transformation processes (Kitahara et al 1984;Rao et al 1987;Ramos-Gomez et al 2001, 2003Frohlich et al 2008).…”