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J. Biol. Chem., Vol. 283, Issue 2, 1179-1188, January 11, 2008

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Tetranor PGDM, an Abundant Urinary Metabolite Reflects Biosynthesis of Prostaglandin D₂ in Mice and Humans^*

From the Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Prostaglandin D₂ (PGD₂) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease. 11,15-Dioxo-9-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD₂ that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD₂ metabolites, 11β-PGF₂ and 2,3-dinor-11β-PGF₂, in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD₂ dose dependently increased urinary tetranor PGDM > 2,3-dinor-11β-PGF₂ > 11β-PGF₂ in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11β-PGF₂ were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD₂ has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11β-PGF₂ in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11β-PGF₂ in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD₂ in humans and mice.

Received for publication, August 16, 2007 , and in revised form, November 7, 2007.

^* This work was supported in part by the Specialized Center in Clinical Research in Vascular Injury (Grant HL 83799), a Clinical and Translational Science Award (RR-023567), and Grant HL R01 073278 (to M. R.) from the National Institutes of Health and by an American Heart Association-Jon Holden DeHann Foundation scientist development grant (to M. W., Y. Y., and T. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S5.

¹ A McNeil Professor in Translational Medicine and Therapeutics. To whom correspondence should be addressed: 153 Johnson Pavilion, School of Medicine, Hamilton Walk, Philadelphia, PA 19104. Tel.: 215-898-1184; Fax: 215-573-9135; E-mail: garret{at}spirit.gcrc.upenn.edu.

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