Animal models for human risk assessment: the peroxisome proliferator-activated receptor alpha-humanized mouse.

The hyperlipidemic fibrate drugs mediate their lipid-lowering effects through binding to and activating the peroxisome proliferator-activated receptor alpha (PPARalpha). PPARalpha ligands are potent hepatocarcinogens in rats and mice; after 11 months of feeding a fibrate drug, there is 100% incidence of adenomas and carcinomas. However, there is no evidence that humans chronically administered fibrates have increased cancer risk. Recent studies on PPARalpha-humanized mice have revealed a potential mechanism for the species differences in response to PPARalpha ligands. These models will be of great value in human risk assessment and in determining the mechanism of hepatocarcinogenesis.