Song Wen-Liang, Wang Miao, Ricciotti Emanuela, Fries Susanne, Yu Ying, Grosser Tilo, Reilly Muredach, Lawson John A, FitzGerald Garret A
Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Biol Chem. 2008 Jan 11;283(2):1179-88. doi: 10.1074/jbc.M706839200. Epub 2007 Nov 8.
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.
前列腺素D2（PGD2）是花生四烯酸的环氧化酶（COX）产物，可激活D类前列腺素受体，在体外调节血管、血小板和白细胞功能。然而，关于其酶促来源或在心血管疾病或炎症性疾病体内的形成知之甚少。通过质谱鉴定，11,15-二氧代-9α-羟基-2,3,4,5-四去甲前列腺素-1,20-二酸（四去甲PGDM）是输注PGD2的一种代谢产物，可在小鼠和人类尿液中检测到。使用液相色谱-串联质谱法，在人类尿液中，四去甲PGDM比PGD2的代谢产物11β-PGF2α和2,3-二去甲-11β-PGF2α丰富得多，并且是在小鼠尿液中唯一可检测到的内源性代谢产物。在小鼠中，输注PGD2剂量依赖性地增加尿中四去甲PGDM＞2,3-二去甲-11β-PGF2α＞11β-PGF2α。脂钙蛋白型或造血PGD合酶的缺失会降低尿中四去甲PGDM。COX-1的缺失或敲低，但不是COX-2的缺失，会降低小鼠尿中四去甲PGDM。相应地，在人类中，PGDM和2,3-二去甲-11β-PGF2α均受到COX-1和COX-2抑制的抑制，但不受COX-2选择性抑制的影响。PGD2与炎症的发生和消退均有关。在志愿者中，给予细菌脂多糖会协同升高四去甲PGDM和2,3-二去甲-11β-PGF2α，同时伴有发热和全身炎症反应，但在消退期两种代谢产物均下降。烟酸会增加人类的四去甲PGDM和2,3-二去甲-11β-PGF2α，同时伴有面部潮红。四去甲PGDM是尿液中一种丰富的代谢产物，反映了人类和小鼠中PGD2的调节生物合成。
