Animal Models for Human Risk Assessment: The Peroxisome Proliferator-Activated Receptor Alpha-Humanized Mouse

Abstract

The hyperlipidemic fibrate drugs mediate their lipid-lowering effects through binding to and activating the peroxisome proliferator-activated receptor alpha (PPARα). PPARα ligands are potent hepatocarcino-gens 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 PPARα-hu-manized mice have revealed a potential mechanism for the species differences in response to PPARα ligands. These models will be of great value in human risk assessment and in determining the mechanism of hepatocarcinogenesis. © 2007 International Life Sciences Institute.