Identification of novel endogenous cytochrome p450 arachidonate metabolites with high affinity for cannabinoid receptors. J Biol Chem 2008 Sep 05;283(36):24514-24
Date
07/09/2008Pubmed ID
18606824Pubmed Central ID
PMC2528993DOI
10.1074/jbc.M709873200Scopus ID
2-s2.0-54049158142 (requires institutional sign-in at Scopus site) 65 CitationsAbstract
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.
Author List
Chen JK, Chen J, Imig JD, Wei S, Hachey DL, Guthi JS, Falck JR, Capdevila JH, Harris RCMESH terms used to index this publication - Major topics in bold
AnimalsArachidonic Acid
CHO Cells
Cricetinae
Cricetulus
Cytochrome P-450 Enzyme System
HL-60 Cells
Humans
Organ Specificity
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
