γ-Glutamyltranspeptidase-negative phenotypic property of preneoplastic and neoplastic liver lesions induced by ciprofibrate does not change following 2-acetylaminofluorene administration

Abstract

Preneoplastic and neoplastic lesions induced by peroxisome proliferators in the livers of rats and mice do not express gamma-glutamyltranspeptidase (GGT). Previous studies have shown that the absence of GGT is not due to the toxic effect of peroxisome proliferators or due to the presence of inactive enzyme. The present experiment was designed to examine whether the GGT-negative property of these lesions is stable and irreversible or whether these lesions can be modulated to express GGT by 2-acetylaminofluorene (AAF). Hepatic lesions were induced in F-344 rats by feeding ciprofibrate (0.025%) in diet for 60 or 84 weeks. These rats were then administered AAF in diet (0.02%) for 5 weeks and the altered areas (AAs), neoplastic nodules (NNs) and hepatocellular carcinomas were analyzed for the expression of GGT. Ninety per cent of carcinomas, 90-100% of NNs and greater than 60% AAs were negative for GGT following AAF treatment. These results are very similar to the phenotypic features observed in the livers of rats treated with ciprofibrate alone. The results of this study suggest that the GGT-negative property of ciprofibrate-induced lesions is stable and not modulatable by AAF.

An overview of peroxisome proliferator-induced hepatocarcinogenesis.

“…The lack of expression of y-glutamyl transpeptidase and glutathione s-transferase-P is not due to drug toxicity or the presence of inactive protein, but is due to failure of derepression of genes encoding for these enzymes (42). The failure of y-glutamyl transpeptidase expression is irreversible and cannot be altered by the administration of genotoxic carcinogens (43). Similar enzyme patterns are also reported in lesions initiated by diethylnitrosamine and promoted by peroxisome proliferators (35,37).…”

Biochemical markers associated with the stages of promotion and progression during hepatocarcinogenesis in the rat.

“…These distinctive phenotypic distributions of AHF resulting from treatment with different promoting agents may be due to the alteration of expression of specific genes within the AHF by a specific promoter (57). This idea has not yet been fully explored, but recent studies by Yeldandi et al (58) suggest that the phenotypic expression induced by promotion with a peroxisorne proliferator is not altered by replacement of this promoter with 2-acetylaminofluorene.…”