Effect of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on eicosanoid concentrations in rat liver.

Abstract

Several hypolipidemic drugs, plasticizers, perfluorinated fatty acids, and other chemicals induce hepatic peroxisomes and hepatocellular carcinomas when administered to rodents (Reddy and Lalwani, 1983). These agents cause hepatocellular carcinomas by an unknown mechanism, which may involve altered lipid metabolism. Peroxisome proliferators markedly increase lipid metabolism through increased expression of several proteins, including enzymes of the peroxisomal fatty acid β-oxidation pathway and cytochrome P4504A1 (Hawkins et al., 1987). Both of these pathways catalyze oxidation of metabolites of the arachidonate pathway. Exposure of rats to peroxisome proliferators enhances the rate of hepatic prostaglandin catabolism (Brass and Ruff, 1991) and co-oxidation of arachidonate metabolites (Capdevila et al., 1992). Several studies suggest that eicosanoids are involved in liver tumor promotion in tats fed a choline-deficient diet (Gupta et al., 1990) and phénobarbital promotion of hepatocarcinogenesis (Denda et al., 1989). Thus, alterations in eicosanoid metabolism may be involved in the promotion of hepatocellular carcinomas by peroxisome proliferators.