Altered hepatic eicosanoid concentrations in rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid.
Several hypolipidemic drugs, plasticizers, and other chemicals induce hepatic peroxisome proliferation and hepatocellular carcinomas in rodents. These agents induce and promote hepatocarcinogenesis by unknown mechanisms, since most studies have not found them to be genotoxic. Peroxisome proliferators increase the expression of several genes, including those for the enzymes of the peroxisomal beta-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids. The peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA) were therefore examined for their ability to alter hepatic eicosanoid concentrations. Rats received injections of 3 or 10 mg PFDA/kg body weight every 14 days or were fed 0.01% ciprofibrate for 10 days, 24 days, 6 weeks, 26 weeks, or 54 weeks. The activity of the peroxisomal enzyme fatty acyl CoA oxidase was significantly increased by both ciprofibrate and PFDA at all times. Hepatic concentrations of prostaglandins E2 and F2a (PGE2, PGF2a), thromboxane B2 (TXB2), and leukotriene C4 (LTC4) were measured by immunoassay. Concentrations of PGE2, PGF2a, and TXB2 were decreased in livers of rats receiving ciprofibrate or PFDA compared to livers of control rats, with ciprofibrate exerting a greater effect than PFDA at the doses used. Hepatic LTC4 concentrations were significantly increased by ciprofibrate at 10 days and PFDA at 54 weeks, and significantly decreased by PFDA at 26 weeks. These alterations in eicosanoid concentrations may be important in the natural history of peroxisome proliferator-induced hepatocarcinogenesis.
Wilson
M W
MW
Department of Nutrition and Food Science, University of Kentucky, Lexington 40506-0054, USA.
Lay
L T
LT
Chow
C K
CK
Tai
H H
HH
Robertson
L W
LW
Glauert
H P
HP
D042962:Acyl-CoA Oxidase; D000818:Animals; D002995:Clofibric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D003652:Decanoic Acids / Q000008:administration & dosage / Q000633:toxicity*; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism*; D058607:Fibric Acids; D005466:Fluorocarbons / Q000008:administration & dosage / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000633:toxicity*; D007118:Immunoassay; D017997:Leukotriene C4 / Q000378:metabolism; D008099:Liver / 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 / Q000378:metabolism
D003652:Decanoic Acids; D015777:Eicosanoids; D058607:Fibric Acids; D005466:Fluorocarbons; D000960:Hypolipidemic Agents; D017997:Leukotriene C4; C036567:perfluorodecanoic acid; D002995:Clofibric Acid; D013929:Thromboxane B2; D015237:Dinoprost; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; C019304:ciprofibrate; D015232:Dinoprostone