REDUCTION OF THE CONCENTRATIONS OF PROSTAGLANDINS E(2) AND F2-ALPHA, AND THROMBOXANE B-2 IN CULTURED RAT HEPATOCYTES TREATED WITH THE PEROXISOME PROLIFERATOR CIPROFIBRATE

Several hypolipidemic drugs, plasticizers and other chemicals induce p eroxisome proliferation and hepatic tumors in rodents, but the mechani sm by which they induce tumors is not fully understood. Their carcinog enic activity may be related to alterations in gene expression, such a s induction of peroxisomal beta-oxidation enzymes or of the cytochrome P450 4A family. These enzymes metabolize lipids, including eicosanoid s and their precursor fatty acids. Because eicosanoids likely play a r ole in the carcinogenic process, alterations in their concentration by xenobiotics may be important in their carcinogenic or promoting activ ities. In this study we used isolated hepatocytes to study if peroxiso me proliferators alter the metabolism of prostaglandins (PG) and throm boxanes (Tx). Isolated rat hepatocytes were cultured for 4 days with 2 concentrations of ciprofibrate (CIP): 100 and 400 mu M. Fatty acyl Co A oxidase activities of the 100 and 400 mu M CIP treatment groups at t he end of the experiment were increased 5.3 and 9.6 times, respectivel y. TxB(2) and PGF(2 alpha) concentrations in cultures treated with CIP were significantly lower than the control at days 3 and 4, whereas a lower concentration of PGE(2) was seen at day 4 only. These studies sh ow that PG and Tx concentrations in cultured hepatocytes are lowered b y the peroxisome proliferator CIP.