Effects of the PPARαAgonist and Widely Used Antihyperlipidemic Drug Gemfibrozil on Hepatic Toxicity and Lipid Metabolism

Abstract

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.

Evaluation of chronic toxicity and carcinogenicity of ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in Sprague–Dawley rats

“…The test chemical belongs to a class of compounds known as peroxisome proliferators (PPARα agonists) which are known to produce liver, pancreatic, and testicular tumors in rats and liver tumors in mice [3] , [16] . However, these compounds have not been shown to be carcinogenic in other species including humans [16] , [7] . Based on the extensive research into the comparative biology of peroxisome proliferator-induced hepatic carcinogenesis, the induction of liver tumors in rodents by non-genotoxic peroxisome proliferators (this compound was shown to be inactive in a battery of genotoxicity assays) is not considered relevant to humans [23] , [7] , [17] .…”

“…However, these compounds have not been shown to be carcinogenic in other species including humans [16] , [7] . Based on the extensive research into the comparative biology of peroxisome proliferator-induced hepatic carcinogenesis, the induction of liver tumors in rodents by non-genotoxic peroxisome proliferators (this compound was shown to be inactive in a battery of genotoxicity assays) is not considered relevant to humans [23] , [7] , [17] . While there is less definitive mechanistic data on the role PPARα plays in the induction of pancreatic acinar cell tumors in rats, the available data involving altered bile flow and increased cholecystokinin suggests that this mode of action is also likely to be non-relevant for humans [16] .…”

Mitochondrial Oxidative Stress Alters a Pathway in Caenorhabditis elegans Strongly Resembling That of Bile Acid Biosynthesis and Secretion in Vertebrates

“…an inhibitor of the HDL receptor SR-BI [24] ), or that reverse cholesterol transport by stimulating gene expression through nuclear hormone receptors (e.g. gemfibrozil [25] ). Thus, although it is not yet known how elevated lipoprotein biosynthesis slows down the defecation cycle, the clk-1 mutants provide a tractable genetic model for characterizing the mechanisms of lipids and sterol uptake and the biosynthesis and secretion of LDL-like lipoproteins.…”

The impact of mitochondrial oxidative stress on bile acid-like molecules inC. elegansprovides a new perspective on human metabolic diseases

“…It is not clear how elevated lipoprotein biosynthesis and secretion slow down the defecation cycle; however, the MTP-dependent lipid transport system appears to be so well conserved between mammals and C. elegans that drugs that have been developed to lower lipid levels in humans can act as suppressors of the slow defecation phenotype of clk-1 mutants 32 . For example, the slow defecation is suppressed by drugs that (1) antagonize high LDL levels by increasing HDL levels (e.g., phenylthiourea inhibitors of the HDL receptor SR-BI 33 ), that (1) stimulate reverse cholesterol transport by regulating gene expression through nuclear hormone receptors (e.g., gemfibrozil 34 ), or that (3) inhibit the activity of HMG-CoA reductase to lower cholesterol levels (e.g., fluvastatin and lovastatin). This suggests that the targets of these drugs are conserved to a sufficient degree in worms for these compounds to be active and that C. elegans provides a pharmacological platform that could be used to develop or identify compounds that affect lipid metabolism in mammals as well.…”