Abstract
Prostaglandin D(2) (PGD(2)) 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-9alpha-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD(2) that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD(2) metabolites, 11beta-PGF(2alpha) and 2,3-dinor-11beta-PGF(2alpha), in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD(2) dose dependently increased urinary tetranor PGDM > 2,3-dinor-11beta-PGF(2alpha) > 11beta-PGF(2alpha) 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-11beta-PGF(2alpha) were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD(2) has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) 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-11beta-PGF(2alpha) in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD(2) in humans and mice.
Highlights
Recent interest in Prostaglandin D2 (PGD2) has been prompted by the use of DP1 blockade as an adjunct to niacin therapy [10] and by the potential role of PGD2 and its metabolites in the resolution of inflammation [11]
We report the identification of a novel D-ring metabolite formed from infused PGD2, 11,15-dioxo-9␣-hydroxy, 2,3,4,5-tetranorprostan-1,20-dioic acid as an abundant endogenous metabolite of PGD2 in both human and mouse urine
Following addition of authentic [2H6]tetranor PGDM to mouse urine, the deuterated compound coeluted with the endogenous material (Fig. 2, A and B)
Summary
Recent interest in PGD2 has been prompted by the use of DP1 blockade as an adjunct to niacin therapy [10] and by the potential role of PGD2 and its metabolites in the resolution of inflammation [11]. A metabolite of PGD2, 15-deoxy-⌬12,14-PGJ2, has been postulated to activate peroxisome proliferator-activated receptor ␥ [14] and promote resolution of an inflammatory infiltrate [11] It remains to be determined by physicochemical methodology whether formation of 15-deoxy-⌬12,14-PGJ2 is augmented during the resolution of human inflammation, and, it can activate PPAR␥, the concentrations required are unlikely to be attained in vivo [15]. Quantitative analysis of the major F-ring metabolite identified in urine after PGD2 infusion in a volunteer, 9␣,11-dihydroxy15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid [19] has been reported in human plasma and urine [22] and reflects nicely the marked augmentation of PGD2 biosynthesis in systemic mastocytosis [4]. Gene manipulations in mice and pharmacological studies in humans implicate COX-1 as the major source of PGD2 as reflected by this metabolite in urine
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