Reduction of the concentrations of prostaglandins E2 and F2alpha, and thromboxane B2 in cultured rat hepatocytes treated with the peroxisome proliferator ciprofibrate.
Several hypolipidemic drugs, plasticizers and other chemicals induce peroxisome proliferation and hepatic tumors in rodents, but the mechanism by which they induce tumors is not fully understood. Their carcinogenic activity may be related to alterations in gene expression, such as induction of peroxisomal beta-oxidation enzymes or of the cytochrome P450 4A family. These enzymes metabolize lipids, including eicosanoids and their precursor fatty acids. Because eicosanoids likely play a role in the carcinogenic process, alterations in their concentration by xenobiotics may be important in their carcinogenic or promoting activities. In this study we used isolated hepatocytes to study if peroxisome proliferators alter the metabolism of prostaglandins (PG) and thromboxanes (Tx). Isolated rate hepatocytes were cultured for 4 days with 2 concentrations of ciprofibrate (CIP): 100 and 400 microM. Fatty acyl CoA oxidase activities of the 100 and 400 microM CIP treatment groups at the end of the experiment were increased 5.3 and 9.6 times, respectively. TxB2 and PGF2alpha concentrations in cultures treated with CIP were significantly lower than the control at days 3 and 4, whereas a lower concentration of PGE2 was seen at day 4 only. These studies show that PG and Tx concentrations in cultured hepatocytes are lowered by the peroxisome proliferator CIP.
Leung
L K
LK
Department of Nutrition and Food Science, University of Kentucky, Lexington 40506-0054, USA.
Glauert
H P
HP
D042962:Acyl-CoA Oxidase; D000704:Analysis of Variance; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D015237:Dinoprost / Q000032:analysis / Q000378:metabolism*; D015232:Dinoprostone / Q000032:analysis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D058607:Fibric Acids; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D000960:Hypolipidemic Agents / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects; D010088:Oxidoreductases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013929:Thromboxane B2 / Q000032:analysis / Q000378:metabolism*
D058607:Fibric Acids; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D013929:Thromboxane B2; D015237:Dinoprost; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; C019304:ciprofibrate; D015232:Dinoprostone