Effects of the PPARα Agonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism.
Gemfibrozil is a widely prescribed hypolipidemic agent in humans and a peroxisome proliferator and liver carcinogen in rats. Three-month feed studies of gemfibrozil were conducted by the National Toxicology Program (NTP) in male Harlan Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters, primarily to examine mechanisms of hepatocarcinogenicity. There was morphologic evidence of peroxisome proliferation in rats and mice. Increased hepatocyte proliferation was observed in rats, primarily at the earliest time point. Increases in peroxisomal enzyme activities were greatest in rats, intermediate in mice, and least in hamsters. These studies demonstrate that rats are most responsive while hamsters are least responsive. These events are causally related to hepatotoxicity and hepatocarcinogenicity of gemfibrozil in rodents via peroxisome proliferator activated receptor-α (PPARα) activation; however, there is widespread evidence that activation of PPARα in humans results in expression of genes involved in lipid metabolism, but not in hepatocellular proliferation.
Cunningham
Michael L
ML
National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
Collins
Bradley J
BJ
Hejtmancik
Milton R
MR
Herbert
Ronald A
RA
Travlos
Gregory S
GS
Vallant
Molly K
MK
Stout
Matthew D
MD