Submitted on January 2, 2007
Accepted on January 17, 2007
The cytochromes P450 CYP2C epoxygenase and CYP4A omega-hydroxylase mediate ciprofibrate-induced PPAR alpha-dependent peroxisomal proliferation in isolated rat liver cells
Arnaldo Gatica, Mauricio C. Aguilera, David Contador, Gloria Loyola, Claudio O. Pinto, Ludwig Amigo, Juan E. Tichauer, Silvana Zanlungo, and Miguel Bronfman
Cell & Molecular Biology, P.Universidad Catolica de Chile, Santiago 6513677
Corresponding Author: mbronfman{at}bio.puc.cl
Peroxisomal proliferators, such as ciprofibrate, are extensively utilized as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisomal proliferator-activated receptor (PPAR) 
subtype of nuclear receptors, and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. Hydroxy-epoxyeicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid by the cytochromes P450 CYP2C epoxygenases and the CYP4A 
-hydroxylases gene sub-families has been identified as potent and high affinity ligands of PPAR in vitro and as PPAR activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A -hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, over-expression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPAR ligands, and that the P450 arachidonic acid monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and activation of PPARdownstream targets.
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