J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M500374-JLR200 on September 8, 2005

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Journal of Lipid Research, Vol. 46, 2745-2751, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Enzymatic formation of prostamide F2{alpha} from anandamide involves a newly identified intermediate metabolite, prostamide H2

Wu Yang1,*, Jinsong Ni*, David F. Woodward{dagger}, Diane D-S. Tang-Liu* and Kah-Hiing John Ling*

* Department of Pharmacokinetics and Drug Metabolism, Allergan, Inc., Irvine, CA 92623
{dagger} Department of Biological Sciences, Allergan, Inc., Irvine, CA 92623

Published, JLR Papers in Press, September 8, 2005. DOI 10.1194/jlr.M500374-JLR200

1 To whom correspondence should be addressed. e-mail: yang_wu{at}allergan.com

Prostaglandin F2{alpha} 1-ethanolamide (prostamide F2{alpha}) 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 F2{alpha}. 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 F2{alpha} 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 F2{alpha} 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 F2{alpha} by PGF synthase. This endoperoxide ethanolamide intermediate has been proposed as prostamide H2.

Supplementary key words cyclooxygenase 2 • prostaglandin F2{alpha} 1-ethanolamide • prostaglandin F synthase


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