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J. Biol. Chem., Vol. 283, Issue 36, 24514-24524, September 5, 2008

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Identification of Novel Endogenous Cytochrome P450 Arachidonate Metabolites with High Affinity for Cannabinoid Receptors^*

Jian-Kang Chen, Jianchun Chen, John D. Imig, Shouzuo Wei, David L. Hachey^¶, Jagadeesh Setti Guthi^||, John R. Falck^||, Jorge H. Capdevila^¶, and Raymond C. Harris^**1

From the Departments of Medicine and ^¶Biochemistry, Vanderbilt University, Nashville, Tennessee 37232, the ^**Department of Veterans Affairs, Nashville, Tennessee 37212, the Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912 and the ^||Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Arachidonic acid is an essential constituent of cell membranes that is esterified to the sn-2-position of glycerophospholipids and is released from selected lipid pools by phospholipase cleavage. The released arachidonic acid can be metabolized by three enzymatic pathways: the cyclooxygenase pathway forming prostaglandins and thromboxanes, the lipoxygenase pathway generating leukotrienes and lipoxins, and the cytochrome P450 (cP450) pathway producing epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids. The present study describes a novel group of cP450 epoxygenase-dependent metabolites of arachidonic acid, termed 2-epoxyeicosatrienoylglycerols (2-EG), including two regioisomers, 2-(11,12-epoxyeicosatrienoyl)glycerol (2-11,12-EG) and 2-(14,15-epoxyeicosatrienoyl)glycerol (2-14,15-EG), which are both produced in the kidney and spleen, whereas 2-11,12-EG is also detected in the brain. Both 2-11,12-EG and 2-14,15-EG activated the two cannabinoid (CB) receptor subtypes, CB1 and CB2, with high affinity and elicited biological responses in cultured cells expressing CB receptors and in intact animals. In contrast, the parental arachidonic acid and epoxyeicosatrienoic acids failed to activate CB1 or CB2 receptors. Thus, these cP450 epoxygenase-dependent metabolites are a novel class of endogenously produced, biologically active lipid mediators with the characteristics of endocannabinoids. This is the first evidence of a cytochrome P450-dependent arachidonate metabolite that can activate G-protein-coupled cell membrane receptors and suggests a functional link between the cytochrome P450 enzyme system and the endocannabinoid system.

Received for publication, December 4, 2007 , and in revised form, July 1, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant Program Project Grant DK38226 (to J.-K. C., J. D. I., J. R. F., J. H. C., and R. C. H.). This work was also supported by the Department of Veterans Affairs (to R. C. H.) and American Heart Association Scientist Development Grant 0630274N (to J.-K. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: S-3223 Medical Center North, Dept. of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-343-0030; Fax: 615-343-2675; E-mail: ray.harris{at}vanderbilt.edu.

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