The peroxisome proliferator-activated receptor alpha (PPARalpha): role in hepatocarcinogenesis

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor superfamily and mediates most of the known biological effects of peroxisome proliferators. The latter represents a large group of chemicals that include the fibrate hyperlipidemic drugs, the pthalate plasticizers, various solvents and degreasing agents, and endogenous hormones and fatty acids. Peroxisome proliferators are classical members of the nongenotoxic group of chemical carcinogens that do not require metabolic activation to electrophiles in order to exert their harmful effects. These chemicals are of particular concern to regulatory agencies since they can only be detected by long-term carcinogen bioassays using rodents. The mechanism of the carcinogenic action of peroxisome proliferators is beginning to emerge. PPARalpha-null mice are resistant to hepatocarcinogenesis indicating that this receptor is necessary for cancer. However, recent studies indicate that Kupffer cells, in a PPARalpha independent manor, are required for the major effects of peroxisome proliferators on cell proliferation. An interaction between PPARalpha and estrogen carcinogenesis has also been elucidated.