Enzymatic formation of prostamide F2alpha from anandamide involves a newly identified intermediate metabolite, prostamide H2.
Prostaglandin F2alpha 1-ethanolamide (prostamide F2alpha) is a potent ocular hypotensive agent in animals and represents a new class of fatty acid amide compounds. Accumulated evidence indicated that anandamide, an endogenous bioactive ligand for cannabinoid receptors, may serve as a common substrate to produce all prostamides, including prostamide F2alpha. After incubation of anandamide with cyclooxygenase 2 (COX-2), the reaction mixture was profiled by HPLC and an intermediate metabolite was discovered and characterized as a cyclic endoperoxide ethanolamide using HPLC-tandem mass spectrometry. Formation of prostamide F2alpha was also demonstrated when the intermediate metabolite was isolated and incubated with prostaglandin F synthase (PGF synthase). These results suggest that the biosynthesis of prostamide F2alpha proceeds in two consecutive steps: oxidation of anandamide to form an endoperoxide intermediate by COX-2, and reduction of the endoperoxide intermediate to form prostamide F2alpha by PGF synthase. This endoperoxide ethanolamide intermediate has been proposed as prostamide H2.
Yang
Wu
W
Department of Pharmacokinetics and Drug Metabolism, Allergan, Inc., Irvine, CA 92623, USA. yang_wu@allergan.com
Ni
Jinsong
J
Woodward
David F
DF
Tang-Liu
Diane D-S
DD
Ling
Kah-Hiing John
KH
D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D063388:Endocannabinoids; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D013058:Mass Spectrometry; D015394:Molecular Structure; D053284:Polyunsaturated Alkamides
D001095:Arachidonic Acids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; C493494:prostaglandin F2alpha ethanolamide; C507368:prostamide H2; D006911:Hydroxyprostaglandin Dehydrogenases; C031051:prostaglandin-F synthase; D051546:Cyclooxygenase 2; D015232:Dinoprostone; C078814:anandamide