Co-carcinogenic effect of cyclohexanol on the development of preneoplastic lesions in a rat hepatocarcinogenesis model

Abstract

Cyclohexanol is a basic industrial chemical widely used because of its versatility as an industrial solvent. No studies have been conducted to evaluate the carcinogenic/co-carcinogenic hazards associated with cyclohexanol exposure. In male Fisher 344 rats liver preneoplastic lesions were induced by N-nitrosodiethylamine (150 mg/Kg) i.p., followed by the tumor promoter 2-acetylaminofluorene (2-AAF: 20 mg/kg) orally administered on three consecutive days before partial hepatectomy. The cyclohexanol administration in this hepatocarcinogenesis assay revealed that it has a strong tumor co-promoter potential. There is clear evidence that oxidative stress and the CYP2E1 are components of carcinogenesis. Although no changes in the lipid peroxidation levels were observed between treated and untreated animals, a significant increase in CYP2E1 expression was observed when cyclohexanol was administered 24 h after the last 2-AAF dose. On the other hand, levels of the proliferation markers PCNA and Ki-67 were not increased after treatment with cyclohexanol, but a marked downregulation of the Bax proapoptotic protein was found exclusively in mitochondrial extracts of animals treated with cyclohexanol. This study represents the first report of the ability of cyclohexanol-induced lesions, when administered simultaneously with 2-AAF, to potentiate the development of preneoplastic liver. © 2007 Wiley-Liss, Inc.