20-Carboxy-arachidonic acid is a dual activator of peroxisome proliferator-activated receptors alpha and gamma

20-Carboxy-arachidonic acid (20-COOH-AA) is a metabolite of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid produced from arachidonic acid by cytochrome P450 (CYP) omega-oxidases. Alcohol dehydrogenases convert 20-HETE to 20-COOH-AA, and we now find that a microsomal preparation containing recombinant human CYP4F3B converts arachidonic acid to 20-HETE and 20-COON-AA. Studies with transfected COS-7 cell expression systems indicate that 20-COOH-AA activates peroxisome proliferators-activated receptor (PPAR) alpha and PPAR gamma. 20-COOH-AA was twice as potent as either 20-HETE or ciglitazone in stimulating PPAR gamma-mediated luciferase expression. While 20-COOH-AA also was more potent than 20-HETE in increasing PPAR alpha-mediated luciferase expression, the increase was only half as much as that produced by Wy-14643. 20-COOH-AA did not increase PPAR alpha or PPAR gamma expression in the transfected cells. Radiolabeled 20-COOH-AA was detected intracellularly when the COS-7 cells were incubated with either [H-3]20-COOH-AA or [H-3]20-HETE, and binding studies indicated that [H-3]20-COOH-AA bound to the isolated ligand binding domains of PPAR alpha (K-d =0.87 0.12 mu M) and PPAR gamma (Ka = 1.7 +/- 0.5 mu M). These findings suggest that 20-COOH-AA, a relatively stable metabolite of 20-HETE, might function as an endogenous dual activator of PPAR alpha and PPAR gamma. (c) 2006 Elsevier Inc. All rights reserved.