Effect of the peroxisome proliferator ciprofibrate on hepatic cyclooxygenase and phospholipase A2 in rats

Peroxisome proliferators, which include several hypolipidemic drugs, plasticizers and other chemicals, induce hepatic tumors in rodents. These chemicals alter the expression of enzymes involved in lipid metabolism, such as the cytochrome P450 4A family and peroxisomal beta-oxidation enzymes. Previous studies have shown that the peroxisome proliferator ciprofibrate reduces eicosanoid concentrations in rat livers and primary hepatocyte cultures, yet the mechanism is still unclear. In this study we examined cyclooxygenases 1 and 2 (COX-1 and COX-2) and cytosolic phospholipase A2 (cPLA2) to determine whether the rate-limiting enzymes in the eicosanoid synthetic pathway are altered by ciprofibrate. Rats were fed 0.01% ciprofibrate for 3, 6, or 10 days. Western analysis revealed that COX-2 protein was induced by ciprofibrate (up to 13-fold at day 10), but that calcium-dependent (Ca-D) cPLA2 protein was not different from controls. The enzyme activity of calcium-independent (Ca-I) cPLA2 in ciprofibrate-treated rats was increased 2-fold, whereas Ca-D cPLA2 and total COX activities were not affected. Using enzyme kinetics, we found that COX-1 (Ki = 143 microM) and Ca-I cPLA2 (Ki = 121 microM) were competitively inhibited by ciprofibrate, but the inhibition was not physiologically significant. COX-2 and Ca-D cPLA2 were not inhibited by ciprofibrate. These results show that ciprofibrate increases Ca-I cPLA2 enzyme activity and COX-2 protein expression.