Mechanisms of Tumor Induction by Peroxisome Proliferators

Peroxisome proliferation is observed as a response, particularly in the liver, to subchronic treatment of rodents with a variety of structurally diverse compounds. This characteristic hepatomegaly was first described in rats treated with the hypolipidemic agent Clofibrate (Hess et al. 1965) and has subsequently been observed in rodents treated with other hypolipidemic agents (Cayen 1985), antiemetics and anti-inflammatories (Ishii and Suga 1979), a leukotriene D4 antagonist (Eacho et al. 1985), herbicides (Moody and Hammock 1987), and plasti-cizers (Warren et al. 1982). Generally treatment of rodents with such compounds results in marked increases in liver weight within a few days, as a consequence of both hyperplasia and hypertrophy. At the subcellular level the hypertrophic hepatocytes show a marked proliferation of the peroxisomal compartment, accompanied by an increase in the amount of smooth endoplasmic reticulum. Biochemically these changes are reflected as an induction of peroxisomal and microsomal enzymes (Bentley et al. 1987a). Lifelong treatment of rodents with several peroxisome proliferators was associated with increased incidences of hepatocellular carcinomas, a finding which led Reddy et al. (1980) to conclude that peroxisome proliferators form a unique class of hepatocarcinogens. These authors proposed a causal link between peroxisome proliferation and carcinogenicity (Fig.1 (discussed below).