Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2
Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2
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DOI：
10.1074/jbc.m007088200
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发表时间：
2000-10-27
影响因子：
4.8
通讯作者：
Marnett, LJ
中科院分区：
文献类型：
--
作者：
Kozak, KR;Rowlinson, SW;Marnett, LJ
环氧合酶（考克斯）通过氧化花生四烯酸为内过氧化物前体的类胡萝卜素和血栓素而在脂质信号转导中起重要作用。存在两种环氧合酶，它们在组织分布和调节上不同，但在其他方面执行相同的化学功能。中性花生四烯酸衍生物，2-花生四烯酸甘油（2-AG），是两个描述的内源性大麻素之一，似乎是一个配体的中央（CB 1）和外周（CB 2）大麻素受体。在这里，我们报告说，2-AG是考克斯-2的底物，它是有效的花生四烯酸代谢。在体外和培养的巨噬细胞中，考克斯-2介导的2-AG氧化提供了新的脂质，前列腺素H-2甘油酯（PGH（2）-G）。由巨噬细胞产生的PGH（2）-G是细胞PGD合成酶的底物，提供PGD（2）-G。药理学研究表明，巨噬细胞从内源性2-AG产生PGD（2）-G是钙依赖性的，并由二酰基甘油脂肪酶和考克斯-2介导。这些结果确定了考克斯-2在内源性大麻素代谢和衍生自二酰基甘油和2-AG的一个新的大麻素家族的产生中的独特功能。
Cyclooxygenases (COX) play an important role in lipid signaling by oxygenating arachidonic acid to endoperoxide precursors of prostaglandins and thromboxane. Two cyclooxygenases exist which differ in tissue distribution and regulation but otherwise carry out identical chemical functions. The neutral arachidonate derivative, 2-arachidonylglycerol (2-AG), is one of two described endocannabinoids and appears to be a ligand for both the central (CB1) and peripheral (CB2) cannabinoid receptors. Here we report that 2-AG is a substrate for COX-2 and that it is metabolized as effectively as arachidonic acid. COX-2-mediated 2-AG oxygenation provides the novel lipid, prostaglandin H-2 glycerol ester (PGH(2)-G), in vitro and in cultured macrophages. PGH(2)-G produced by macrophages is a substrate for cellular PGD synthase, affording PGD(2)-G. Pharmacological studies reveal that macrophage production of PGD(2)-G from endogenous sources of 2-AG is calcium-dependent and mediated by diacylglycerol Lipase and COX-2. These results identify a distinct function for COX-2 in endocannabinoid metabolism and in the generation of a new family of prostaglandins derived from diacylglycerol and 2-AG.