Peroxisome proliferation and hepatocarcinogenesis

Peroxisome proliferators constitute a novel class of non-mutagenic hepatocarcinogens, all of which induce a similar pleiotropic response consisting of hepatomegaly, proliferation of peroxisomes in the liver parenchyma] cells and the induction of several hepatic enzymes, particularly those of the peroxisomal fatty acid /3oxidation system (1—3). Presently several structurally dissimilar hypolipidemic compounds, including the widely used drug clofibrate, and certain phthalate ester plasticizers are the two major categories of agents that are recognized as peroxisome proliferators (2). The lack of mutagenicity of these agents led to the proposal that hepatocarcinogenesis is not related to the direct initiating effect of these chemicals (or their possible metabolites), but linked to metabolic disturbance(s) emanating from sustained increase in the number of peroxisomes in liver cells (4). Elucidation of the mechanism of induction of peroxisome proliferation and associated enzymes by these agents is, therefore, considered essential in order to understand the role of peroxisomes in liver carcinogenesis induced by these xenobiotics which do not appear to interact with and damage DNA (5,6). This commentary is a brief review of the biological effects of peroxisome proliferators and of possible mechanisms of induction of pleiotropic responses leading to the development of hepatocellular carcinomas, focusing in particular on the hypothesis that these agents exert their effects by interacting with a specific receptor(s).