Altered hepatic eicosanoid concentrations in rats treated with the peroxisome proliferators ciprofibrate and perfluorodecanoic acid

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 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.

Evaluation of the incidence and risk factors for development of fenofibrate-associated nephrotoxicity

“…Fenofibrate down-regulates the expression of the inducible cyclo-oxygenase-2 enzyme, which is essential for maintenance of prostaglandins. 30,31 This decreases dilation of the afferent arteriole and compromises glomerular capillary pressure and perfusion of the kidneys. 1,4 In diabetic rat models, reduction in prostaglandin production was coupled with a small decrease in GFR.…”

Effects of high dose aleglitazar on renal function in patients with type 2 diabetes

“…Several potential mechanisms have been proposed whereby fibrates may impair renal function. PPARα activation may inhibit the production of renal vasodilatory prostaglandins [7,21] by down-regulation of cyclooxygenase-2 levels [22,23], eventually negatively affecting glomerular hemodynamics and filtration rate. Alternatively, creatininemia may reflect increases in net daily creatinine production [20].…”

Induction of Cyclooxygenase-2 Expression by Peroxisome Proliferators and Non-tetradecanoylphorbol 12,13-Myristate-type Tumor Promoters in Immortalized Mouse Liver Cells

“…PPs have been found to cause a decrease in hepatic prostaglandin concentrations (54), but their effect on prostaglandin synthesis and COX-2 expression in preneoplastic cells and liver tumors remains to be determined.…”