Altered hepatic eicosanoid concentrations in rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid |
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Authors: | Mary W Wilson L Travis Lay Ching K Chow Hsin -Hsiung Tai Larry W Robertson Howard P Glauert |
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Institution: | (1) Department of Nutrition and Food Science, University of Kentucky, 219 Funkhouser Building, Lexington, KY 40506-0054, USA, US;(2) Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40506, USA, US;(3) College of Pharmacy, University of Kentucky, Lexington, KY 40506, USA, US |
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Abstract: | 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 β-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 F2α (PGE2, PGF2α), thromboxane B2 (TXB2), and leukotriene C4 (LTC4) were measured by immunoassay. Concentrations of PGE2, PGF2α, 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.
Received: 15 September 1994/Accepted: 15 December 1994 |
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Keywords: | Ciprofibrate Perfluorodecanoic acid Eicosanoids Peroxisome |
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