Preneoplastic Changes During Non-Genotoxic Hepatocarcinogenesis

Abstract

Potential new drugs undergo in vitro genotoxicity tests early in their development program and those found to be positive are usually screened out.Hence, compounds tested in preclinical carcinogenicity studies are usually non-genotoxic. The non-genotoxicity of a compound is operationally defined by l)its inability to cause mutations in several bacterial chromatid exchange and 2) its inability to produce covalent DNA adducts or induce DNA repair (measured as unscheduled DNA synthesis). Genotoxic agents are believed to directly affect the genes controlling cell growth and differentiation or the regulatory sequences that control them, and pose a significant risk at any level of exposure. Non-genotoxic carcinogens on the other hand act via indirect or epigenetic mechanisms related to alterations of gene expression.Their effects are believed to be thresholded and to occur only at high or cytotoxic concentrations. Thus, the significance of non-genotoxic carcinogens in terms of human safety is highly disputed and there is real need for a better understanding of the underlying mechanisms. Non-genotoxic carcinogens include mitogenic agents such as TSH, peroxisome proliferators such as fibrate and hypolipaedemic drugs, synthetic estrogens, phorbol esters and phenobarbitone.