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Originally published In Press as doi:10.1074/jbc.M201575200 on July 17, 2002

J. Biol. Chem., Vol. 277, Issue 38, 35105-35112, September 20, 2002
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The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands*

L. Ashley CowartDagger , Shouzuo Wei§, Mei-Hui Hsu, Eric F. Johnson, Murali U. Krishna||, John R. Falck||, and Jorge H. CapdevilaDagger §**

From the Departments of § Medicine and Dagger  Biochemistry, Vanderbilt University Medical School, Nashville, Tennessee 37232, the  Division of Biochemistry, Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037, and the || Department of Biochemistry, Southwestern Medical Center, Dallas, Texas 75390

Cytochromes P450 of the CYP2C and CYP4A gene subfamilies metabolize arachidonic acid to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) and to 19- and 20-hydroxyeicosatetraenoic acids (HETEs), respectively. Abundant functional studies indicate that EETs and HETEs display powerful and often opposing biological activities as mediators of ion channel activity and regulators of vascular tone and systemic blood pressures. Incubation of 8,9-, 11,12-, and 14,15-EETs with microsomal and purified forms of rat CYP4A isoforms led to rapid NADPH-dependent metabolism to the corresponding 19- and 20-hydroxylated EETs. Comparisons of reaction rates and catalytic efficiency with those of arachidonic and lauric acids showed that EETs are one of the best endogenous substrates so far described for rat CYP4A isoforms. CYP4A1 exhibited a preference for 8,9-EET, whereas CYP4A2, CYP4A3, and CYP4A8 preferred 11,12-EET. In general, the closer the oxido ring is to the carboxylic acid functionality, the higher the rate of EET metabolism and the lower the regiospecificity for the EET omega -carbon. Analysis of cis-parinaric acid displacement from the ligand-binding domain of the human peroxisome proliferator-activated receptor-alpha showed that omega -hydroxylated 14,15-EET bound to this receptor with high affinity (Ki = 3 ± 1 nM). Moreover, at 1 µM, the omega -alcohol of 14,15-EET or a 1:4 mixture of the omega -alcohols of 8,9- and 11,12-EETs activated human and mouse peroxisome proliferator-activated receptor-alpha in transient transfection assays, suggesting a role for them as endogenous ligands for these orphan nuclear receptors.

* This work was supported by NIGM Grants 37922 (to J. H. C.) and 31278 (to J. R. F.) and Grant HD04445 (to E. F. J.) from the United States Public Health Service, NIDDK Grant 38226 (to J. H. C. and to J. R. F.) from the National Institutes of Health, National Research Service Award Grant HL07323-(18-21) (to L. A. C.), and the Robert A. Welch Foundation (to J. R. F).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Medicine, Vanderbilt University Medical School, Medical Center North S-3223, 1161 21st Ave. South, Nashville, TN 37232. Tel.: 615-322-4968; Fax: 615-343-4704; E-mail: jorge.capdevila@mcmail.vanderbilt.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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