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 β-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 (K(i) = 143 μM) and Ca-I cPLA2 (K(i) = 121 μM) 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.
|Number of pages||9|
|State||Published - Feb 20 1998|
Bibliographical noteFunding Information:
This research was supported by NIH grants CA74147 and CA01688 and by the Kentucky Agricultural Experiment Station (KAES journal article no. 97-10-47). The human cPLA 2 protein and antibodies were gifts from the Genetics Institute, Cambridge, MA. Ciprofibrate was a gift from Sanofi Research, Malvern, PA.
- Phospholipase A
ASJC Scopus subject areas