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.