title: Metabolism of the endocannabinoids, 2-arachidonylglycerol and anandamide, into prostaglandin, thromboxane, and prostacyclin glycerol esters and ethanolamides.
abstract: Cyclooxygenase-2 (COX-2) action on the endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), generates prostaglandin glycerol esters (PG-G) and ethanolamides (PG-EA), respectively. The diversity of PG-Gs and PG-EAs that can be formed enzymatically following COX-2 oxygenation of endocannabinoids was examined in cellular and subcellular systems. In cellular systems, glycerol esters and ethanolamides of PGE(2), PGD(2), and PGF(2alpha) were major products of the endocannabinoid-derived COX-2 products, PGH(2)-G and PGH(2)-EA. The sequential action of purified COX-2 and thromboxane synthase on AEA and 2-AG provided thromboxane A(2) ethanolamide and glycerol ester, respectively. Similarly, bovine prostacyclin synthase catalyzed the isomerization of the intermediate endoperoxides, PGH(2)-G and PGH(2)-EA, to the corresponding prostacyclin derivatives. Quantification of the efficiency of prostaglandin and thromboxane synthase-directed endoperoxide isomerization demonstrated that PGE, PGD, and PGI synthases catalyze the isomerization of PGH(2)-G at rates approaching those observed with PGH(2). In contrast, thromboxane synthase was far more efficient at catalyzing PGH(2) isomerization than at catalyzing the isomerization of PGH(2)-G. These results define the in vitro diversity of endocannabinoid-derived prostanoids and will permit focused investigations into their production and potential biological actions in vivo.
authors.affiliation: Department of Biochemistry, Vanderbilt-Ingram Cancer Center, and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Lee-Ho
authors.initials: LH
authors.lastname: Wang
authors.forename: Y Henry
authors.initials: YH
authors.lastname: Ma
authors.forename: Rolf
authors.initials: R
authors.lastname: Weinander
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D002417:Cattle; D002460:Cell Line; D051546:Cyclooxygenase 2; D063388:Endocannabinoids; D011464:Epoprostenol / Q000378:metabolism*; D004952:Esters / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D054834:Lipocalins; D008565:Membrane Proteins; D051379:Mice; D015394:Molecular Structure; D018377:Neurotransmitter Agents / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D013237:Stereoisomerism; D013930:Thromboxane-A Synthase / Q000378:metabolism; D013931:Thromboxanes / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D004952:Esters; D005989:Glycerides; D007527:Isoenzymes; D054834:Lipocalins; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; D053284:Polyunsaturated Alkamides; D011453:Prostaglandins; D013931:Thromboxanes; C094503:glyceryl 2-arachidonate; D011464:Epoprostenol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D013930:Thromboxane-A Synthase; D005990:Glycerol; C078814:anandamide