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.
Gonzalez
Frank J
FJ
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. fjgonz@helix.nih.gov
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000473:pathology*; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism*; D018570:Risk Assessment / Q000379:methods*; D013045:Species Specificity
D047493:PPAR alpha