Peroxisome proliferators: their biological and toxicological effects

One of the most rapidly developing areas of organelle biology, which has a major involvement in biochemical pharmacology, is the research into the peroxisomal function. There is a large group of compounds that are capable of inducing liver enlargement, proliferation of peroxisomal structures, and induction of peroxisomal and extraperoxisomal fatty acid-oxidizing enzymes in rodent liver, called peroxisome proliferators. This list includes hypolipidemic drugs, analgesics, uricosuric drugs, environmental pollutants, phthalates, etc. Some peroxisome proliferators have also been shown to increase the incidence of liver tumors. This review describes the characteristics of peroxisome proliferation in rodent liver and gives examples 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. Rodent peroxisome proliferators are not considered to be genotoxic agents. Proposed mechanisms of liver tumor formation include induction of sustained oxidative stress, enhanced cell replication, promotion of spontaneous preneoplastic lesions, and inhibition of apoptosis. In addition, the absence of effects of peroxisome proliferators on peroxisome proliferator-associated parameters supports the hypothesis that human liver cells are refractory to peroxisome proliferator-induced hepatic carcinogenesis.