MECHANISM OF ACTION OF THE NONGENOTOXIC PEROXISOME PROLIFERATORS - ROLE OF CHE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA

Peroxisome proliferators are a diverse group of chemicals that include several therapeutically used drugs (e.g., hypolipidemic agents), plas ticizers and organic solvents used in the chemical industry, herbicide s, and naturally occurring hormones. As the name implies, peroxisome p roliferators cause an increase in the number and size of peroxisomes i n the liver, kidney, and heart tissue of susceptible species, such as rats and mice. Long-term administration of peroxisome proliferators ca n cause liver cancer in these animals, a response that has been the ce ntral issue of research on peroxisome proliferators for many years, Pe roxisome proliferators are representative of the class of nongenotoxic carcinogens that cause cancer through mechanisms that do not involve direct DNA damage, The fact that humans are frequently exposed to thes e agents makes them of particular concern to government regulatory age ncies responsible for assuring human safety, Whether frequent exposure to peroxisome proliferators represents a hazard to humans is unknown; however, increased cancer risk has not been shown to be associated wi th long-term therapeutic administration of the hypolipidemic drugs gem fibrozil, fenofibrate, and clofibrate, To make sound judgments regardi ng the safety of peroxisome proliferators, the validity of extrapolati ng results from rodent bioassays to humans must be based on the agents ' mechanism of action and species differences in biologic activity and carcinogenicity, The peroxisome proliferator-activated receptor alpha (PPAR alpha), a member of the nuclear receptor superfamily, has been found to mediate the activity of peroxisome proliferators in mice. Gen e-knockout mice lacking PPAR alpha are refractory to peroxisome prolif eration and peroxisome proliferator-induced changes in gene expression , Furthermore, PPAR alpha-null mice are resistant to hepatocarcinogene sis when fed a diet containing a potent nongenotoxic carcinogen WY-14, 643. Recent studies have revealed that humans have considerably lower levels of PPAR alpha in liver than rodents, and this difference may, i n part, explain the species differences in the carcinogenic response t o peroxisome proliferators.