title: Endocannabinoids and their oxygenation by cyclo-oxygenases, lipoxygenases and other oxygenases.
abstract: The naturally occurring mammalian endocannabinoids possess biological attributes that extend beyond interaction with cannabinoid receptors. These extended biological properties are the result of oxidative metabolism of the principal mammalian endocannabinoids arachidonoyl ethanolamide (anandamide; A-EA) and 2-arachidonoylglycerol (2-AG). Both endocannabinoids are oxidized by cyclo-oxygenase-2 (COX-2), but not by COX-1, to a series of prostaglandin derivatives (PGs) with quite different biological properties from those of the parent substrates. PG ethanolamides (prostamides, PG-EAs) and PG glyceryl esters (PG-Gs) are not only pharmacologically distinct from their parent endocannabinoids, they are distinct from the corresponding acidic PGs, and are differentiated from each other. Ethanolamides and glyceryl esters of the major prostanoids PGD2, PGE2, PGF2α, and PGI2 are formed by the various PG synthases, and thromboxane ethanolamides and glyceryl esters are not similarly produced. COX-2 is also of interest by virtue of its corollary central role in modulating endocannabinoid tone, providing a new therapeutic approach for treating pain and anxiety. Other major oxidative conversion pathways are provided for both A-EA and 2-AG by several lipoxygenases (LOXs), resulting in the formation of numerous hydroxyl metabolites. These do not necessarily represent inactivation pathways for endocannabinoids but may mimic or modulate the endocannabinoids or even display alternative pharmacology. Similarly, A-EA and 2-AG may be oxidized by P450 enzymes. Again a very diverse number of metabolites are formed, with either cannabinoid-like biological properties or an introduction of disparate pharmacology. The biological activity of epoxy and hydroxyl derivatives of the endocannabinoids remains to be fully elucidated. This review attempts to consolidate and compare the findings obtained to date in an increasingly important research area. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".
authors.affiliation: Manchester Pharmacy School, Faculty of Medical and Human Sciences, Stopford Building, Oxford Road, The University of Manchester, M13 9PT, UK.
authors.forename: P
authors.initials: P
authors.lastname: Urquhart
authors.affiliation: Manchester Pharmacy School, Faculty of Medical and Human Sciences, Stopford Building, Oxford Road, The University of Manchester, M13 9PT, UK. Electronic address: anna.nicolaou@manchester.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Nicolaou
authors.affiliation: Dept of Biological Sciences, Allergan, Inc., Irvine, CA 92612, USA.
authors.forename: D F
authors.initials: DF
authors.lastname: Woodward
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D019856:Ethanolamine / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes; D008084:Lipoxygenase / Q000378:metabolism*; D010084:Oxidation-Reduction; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D004852:Epoxy Compounds; D005989:Glycerides; D007527:Isoenzymes; D053284:Polyunsaturated Alkamides; D019856:Ethanolamine; C094503:glyceryl 2-arachidonate; D003577:Cytochrome P-450 Enzyme System; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; C078814:anandamide
keywords: 2-Arachidonyl glycerol ester; Anandamide; Cyclo-oxygenase-2; Cytochrome P450 oxygenase; Lipoxygenase; Prostaglandin glyceryl ester; Prostamide