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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 from anandamide involves a newly identified intermediate metabolite, prostamide H₂

Wu Yang^1,*, Jinsong Ni^*, David F. Woodward, Diane D-S. Tang-Liu^* and Kah-Hiing John Ling^*

^* Department of Pharmacokinetics and Drug Metabolism, Allergan, Inc., Irvine, CA 92623
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 1-ethanolamide (prostamide F₂) 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. 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 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 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 by PGF synthase. This endoperoxide ethanolamide intermediate has been proposed as prostamide H₂.

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

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