Mechanisms of Hepatocarcinogenicity of Peroxisome-Proliferating Drugs and Chemicals

A wide variety of chemicals have been shown to produce liver enlargement, peroxisome proliferation, and induction of peroxisomal and microsomal fatty acid-oxidizing enzyme activities in rats and mice. Moreover, certain peroxisome proliferators have been shown to increase the incidence of liver tumors in these two species. This review describes the characteristics of peroxisome proliferation in rodent liver and in vitro in primary hepatocyte cultures and gives examples of the range of different classes of chemicals that produce this effect. Mechanisms of initiation of peroxisome proliferation in rodent hepatocytes, including peroxisome proliferator-activated receptors, are also described. Peroxisome proliferators are not considered to be genotoxic carcinogens, and proposed mechanisms of liver tumor formation include induction of sustained oxidative stress, a role for enhanced cell replication, and the promotion of spontaneous preneoplastic lesions. Data are also presented on species differences in response and key issues concerning the risk assessment to humans of rodent liver peroxisome proliferators.