Identification of novel endogenous cytochrome P450 arachidonate metabolites with high affinity for cannabinoid receptors
Identification of novel endogenous cytochrome P450 arachidonate metabolites with high affinity for cannabinoid receptors
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DOI：
10.1074/jbc.m709873200
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发表时间：
2008-09-05
影响因子：
4.8
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
--
作者：
Chen, Jian-Kang;Chen, Jianchun;Harris, Raymond C.
花生四烯酸是细胞膜的重要组成部分，其被酯化到甘油磷脂的sn-2-位，并通过磷脂酶裂解从选定的脂质池中释放。释放的花生四烯酸可以通过三种酶途径代谢：形成花生四烯酸和血栓烷的环氧合酶途径，产生白三烯和脂氧素的脂氧合酶途径，以及产生环氧二十碳三烯酸和羟基二十碳四烯酸的细胞色素P450（cP 450）途径。本研究描述了一组新的花生四烯酸cP 450环氧酶依赖性代谢产物，称为2-epoxyeicosatrienoylglycerols（2-EG），包括两个区域异构体，2-（11，12-环氧二十碳三烯酰基）甘油（2- 11，12-EG）和2-（14，15-环氧二十碳三烯酰基）甘油（2- 14，15-EG），它们都在肾脏和脾脏中产生，而2- 11，12-EG也在大脑中检测到。2- 11，12-EG和2- 14，15-EG均以高亲和力激活两种大麻素（CB）受体亚型CB 1和CB 2，并在表达CB受体的培养细胞和完整动物中引起生物学应答。相反，亲本花生四烯酸和环氧二十碳三烯酸未能激活CB 1或CB 2受体。因此，这些cP 450环氧酶依赖性代谢物是一类新的内源性产生的，具有内源性大麻素特征的生物活性脂质介质。这是细胞色素P450依赖的花生四烯酸代谢物，可以激活G-蛋白偶联的细胞膜受体，并表明细胞色素P450酶系统和内源性大麻素系统之间的功能联系的第一个证据。
Arachidonic acid is an essential constituent of cell membranes that is esterified to the sn-2-position of glycerophospholipids and is released from selected lipid pools by phospholipase cleavage. The released arachidonic acid can be metabolized by three enzymatic pathways: the cyclooxygenase pathway forming prostaglandins and thromboxanes, the lipoxygenase pathway generating leukotrienes and lipoxins, and the cytochrome P450 (cP450) pathway producing epoxyeicosatrienoic acids and hydroxyeicosatetraenoic acids. The present study describes a novel group of cP450 epoxygenase-dependent metabolites of arachidonic acid, termed 2-epoxyeicosatrienoylglycerols (2-EG), including two regioisomers, 2-(11,12-epoxyeicosatrienoyl) glycerol (2-11,12-EG) and 2-(14,15-epoxyeicosatrienoyl)glycerol (2-14,15-EG), which are both produced in the kidney and spleen, whereas 2-11,12-EG is also detected in the brain. Both 2-11,12-EG and 2-14,15-EG activated the two cannabinoid (CB) receptor subtypes, CB1 and CB2, with high affinity and elicited biological responses in cultured cells expressing CB receptors and in intact animals. In contrast, the parental arachidonic acid and epoxyeicosatrienoic acids failed to activate CB1 or CB2 receptors. Thus, these cP450 epoxygenase-dependent metabolites are a novel class of endogenously produced, biologically active lipid mediators with the characteristics of endocannabinoids. This is the first evidence of a cytochrome P450-dependent arachidonate metabolite that can activate G-protein-coupled cell membrane receptors and suggests a functional link between the cytochrome P450 enzyme system and the endocannabinoid system.