8,9-epoxy-5,11,14-eicosatrienoic acid ethanolamide

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 8,9-epoxy-5,11,14-eicosatrienoic acid ethanolamide
• 英文别名: 8(9)-EpETrE-EA；(Z)-N-(2-hydroxyethyl)-7-[3-[(2Z,5Z)-undeca-2,5-dienyl]oxiran-2-yl]hept-5-enamide
• 化学式: C₂₂H₃₇NO₃
• 分子量: 363.541
• InChiKey: BXHPMUQFGGSDAK-TYAUOURKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  16
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  61.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  大麻素 在 cytochrome P₄₅₀ reductase 、 cytochrome P₄₅₀ 2J₂ 、 还原型辅酶II(NADPH)四钠盐 作用下， 以 aq. phosphate buffer 为溶剂， 反应 0.5h， 生成 14,15-epoxy-5,8,11-eicosatrienoic acid ethanolamide 、 11,12-epoxy-5,8,14-eicosatrienoic acid ethanolamide 、 8,9-epoxy-5,11,14-eicosatrienoic acid ethanolamide
  参考文献：
  名称：

  Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2

  摘要：

  Phytocannabinoids have well-known cardiovascular implications. For instance, Delta 9-tetrahydrocannabinol (Delta 9-THC), the principal component of cannabis, induces tachycardia in humans. In order to understand the impact of phytocannabinoids on human cardiovascular health, there is a need to study the metabolism of phytocannabinoids by cardiac cytochromes p450 (CYPs). CYP2J2, the primary CYP of cardiomyocytes, is responsible for the metabolism of the endocannabinoid, anandamide (AEA), into cardioprotective epoxides (EET-EAs). Herein, we have investigated the kinetics of the direct metabolism of six phytocannabinoids (Delta 9-THC, Delta 8-tetra-hydrocannabinol, cannabinol, cannabidiol, cannabigerol, and cannabichromene) by CYP2J2. CYP2J2 mainly produces 1'/1 ''-OH metabolites of these phytocannabinoids. These phytocannabinoids are metabolized with greater catalytic efficiency compared to the metabolism of AEA by CYP2J2. We have also determined that the phytocannabinoids are potent inhibitors of CYP2J2-mediated AEA metabolism, with Delta 9-THC being the strongest inhibitor. Most of the inhibition of CYP2J2 by the phytocannabinoids follow a noncompetitive inhibition model, and therefore dramatically reduce the formation of EET-EAs by CYP2J2. Taken together, these data demonstrate that phytocannabinoids are directly metabolized by CYP2J2 and inhibit human cardiac CYP2J2, leading to a reduction in the formation of cardioprotective EET-EAs.

  DOI：

  10.1016/j.jinorgbio.2018.03.016

文献信息

• Effects of a Commonly Occurring Genetic Polymorphism of Human CYP3A4 (I118V) on the Metabolism of Anandamide
  作者：Matthew Pratt-Hyatt、Haoming Zhang、Natasha T. Snider、Paul F. Hollenberg

  DOI：10.1124/dmd.110.033712

  日期：2010.11

  The endocannabinoid system plays an important role in numerous physiological processes including mood, appetite, and pain sensation. A critical compound in maintaining cannabinoid tone is the endocannabinoid anandamide (AEA). We have recently shown that AEA is metabolized by several different human cytochromes P450 (P450) to form a number of metabolites, one of which exhibits increased biological activity. CYP3A4, one of the major P450s involved in the metabolism of AEA, produces four major metabolites. One of these metabolites, 5,6-epoxyeicosatrienoic acid ethanolamide (5,6-EET-EA), exhibits a much higher affinity than AEA for the cannabinoid 2 receptor (CB-2), which leads to a marked decrease in intracellular cAMP levels in cells expressing CB-2. There are multiple human alleles of CYP3A4, and the CYP3A4.4 allele has been shown to exhibit a significant decrease in activity. Recombinant CYP3A4*4 was expressed in Escherichia coli and was demonstrated to produce 60% less 6-hydroxytestosterone than the wild-type (WT) 3A4 in a reconstituted system. The metabolism of AEA by the WT and the CYP3A4.4 variant was investigated. The mutant produced 60% less of the four EET-EA metabolites than the WT. The mutant also produced a new peak on liquid chromatography-mass spectrometry not seen with the WT, which corresponded to 19-hydroxyeicosatetraenoic acid-ethanolamide. In addition, the mutant produces four novel peaks at m/z 380, which correspond to the addition of two oxygen atoms, possibly to form a peroxide bond. These data indicate that individuals expressing the CYP3A4.4 allele may exhibit significant variations in the metabolism of AEA as well as any other compounds resembling AEA.

  内源性大麻素系统在情绪、食欲和痛觉等众多生理过程中发挥着重要作用。维持大麻素张力的一种关键化合物是内源性大麻酰胺（AEA）。我们最近的研究表明，AEA 会被几种不同的人类细胞色素 P450（P450）代谢，形成多种代谢物，其中一种代谢物的生物活性更高。CYP3A4 是参与 AEA 代谢的主要 P450 之一，可产生四种主要代谢物。其中一种代谢物是 5,6-环氧苦辛三烯酸乙醇酰胺（5,6-EET-EA），它对大麻素 2 受体（CB-2）的亲和力远高于 AEA，从而导致表达 CB-2 的细胞中细胞内 cAMP 水平明显下降。人类有多种 CYP3A4 等位基因，CYP3A4.4 等位基因的活性显著降低。在大肠杆菌中表达重组 CYP3A4*4，结果表明在重组系统中产生的 6-羟基睾酮比野生型（WT）3A4 少 60%。研究了 WT 和 CYP3A4.4 变体对 AEA 的代谢。突变体产生的四种 EET-EA 代谢物比 WT 少 60%。突变体还在液相色谱-质谱分析中产生了一个新的峰值，这是 WT 所没有的，它对应于 19-hydroxyeicosatetraenoic acid-ethanolamide。此外，突变体在 m/z 380 处产生了四个新的峰，对应于两个氧原子的添加，可能是为了形成过氧化物键。这些数据表明，表达 CYP3A4.4 等位基因的个体在代谢 AEA 以及任何其他类似 AEA 的化合物时可能会表现出显著的差异。
• Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6
  作者：Chitra Sridar、Natasha T. Snider、Paul F. Hollenberg

  DOI：10.1124/dmd.110.036707

  日期：2011.5

  20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 14,15-epoxyeicosatetraenoic acid ethanolamide (14,15-EET-EA). Pharmacological studies showed that both 20-HETE-EA and 14,15-EET-EA bind to the rat brain cannabinoid CB1 receptor with lower affinities relative to that of anandamide. In addition, both products are degraded more rapidly than anandamide in rat brain homogenates. Their degradation

  Anandamide 是一种花生四烯酸衍生的内源性大麻素，可调节中枢神经系统和外周的正常生理功能和病理生理反应。几种细胞色素 P450 (P450) 亚型代谢 anandamide，形成羟基化和环氧化产物。人类 CYP2B6 和 CYP2D6 在整个大脑中异质表达，表现出临床上显着的多态性，并受外部因素（如酒精和吸烟）的调节。这两种 P450 对 anandamide 的氧化代谢可能对内源性大麻素系统信号传导具有重要的功能影响。在这项研究中，我们研究了野生型 CYP2B6 (2B6.1) 和 CYP2D6 (2D6.1) 及其常见的多态性突变体 2B6.4、2B6.6、2B6.9 和 2D6.34 对 anandamide 的代谢。两种亚型及其突变体在花生四烯酸代谢方面的主要差异是在体外发现 20-羟基二十碳四烯酸乙醇酰胺 (20-HETE-EA) 和 14,15-环氧二十碳四烯酸乙醇酰胺
• The Endocannabinoid Anandamide Is a Substrate for the Human Polymorphic Cytochrome P450 2D6
  作者：Natasha T. Snider、Matthew J. Sikora、Chitra Sridar、Thomas J. Feuerstein、James M. Rae、Paul F. Hollenberg

  DOI：10.1124/jpet.108.141796

  日期：2008.11

  Members of the cytochrome P450 (P450) family of drug-metabolizing enzymes are present in the human brain, and they may have important roles in the oxidation of endogenous substrates. The polymorphic CYP2D6 is one of the major brain P450 isoforms and has been implicated in neurodegeneration, psychosis, schizophrenia, and personality traits. The objective of this study was to determine whether the endocannabinoid arachidonoylethanolamide (anandamide) is a substrate for CYP2D6. Anandamide is the endogenous ligand to the cannabinoid receptor CB1, which is also activated by the main psychoactive component in marijuana. Signaling via the CB1 receptor alters sensory and motor function, cognition, and emotion. Recombinant CYP2D6 converted anandamide to 20-hydroxyeicosatetraenoic acid ethanolamide and 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EET-EAs) with low micromolar K m values. CYP2D6 further metabolized the epoxides of anandamide to form novel dioxygenated derivatives. Human brain microsomal and mitochondrial preparations metabolized anandamide to form hydroxylated and epoxygenated products, respectively. An inhibitory antibody against CYP2D6 significantly decreased the mitochondrial formation of the EET-EAs. To our knowledge, anandamide and its epoxides are the first eicosanoid-like molecules to be identified as CYP2D6 substrates. Our study suggests that anandamide may be a physiological substrate for brain mitochondrial CYP2D6, implicating this polymorphic enzyme as a potential component of the endocannabinoid system in the brain. This study also offers support to the hypothesis that neuropsychiatric phenotype differences among individuals with genetic variations in CYP2D6 could be ascribable to interactions of this enzyme with endogenous substrates.

  细胞色素P450（P450）药物代谢酶家族成员存在于人脑中，它们可能在内源性底物的氧化中发挥重要作用。多态性CYP2D6是主要的脑P450同工型之一，与神经变性、精神病、精神分裂症和人格特质有关。这项研究的目的是确定内源性大麻素花生四烯乙醇酰胺（anandamide）是否是CYP2D6的底物。Anandamide是大麻素受体CB1的内源性配体，它也可以被大麻中的主要精神活性成分激活。通过CB1受体传递的信号会改变感觉和运动功能、认知和情绪。重组CYP2D6将anandamide转化为20-羟基二十碳四烯酸乙醇酰胺和5,6-、8,9-、11,12-和14,15-环氧二十碳三烯酸乙醇酰胺（EET-EAs），其K m值较低。CYP2D6进一步代谢anandamide的环氧化物，形成新的双氧衍生物。人脑微粒体和线粒体制剂分别将anandamide代谢为羟基化和环氧化的产物。针对CYP2D6的抑制性抗体显著降低了线粒体形成的EET-EAs。据我们所知，anandamide及其环氧化物是首批被确定为CYP
• Cross-talk of cannabinoid and endocannabinoid metabolism is mediated via human cardiac CYP2J2
  作者：William R. Arnold、Austin T. Weigle、Aditi Das

  DOI：10.1016/j.jinorgbio.2018.03.016

  日期：2018.7

  Phytocannabinoids have well-known cardiovascular implications. For instance, Delta 9-tetrahydrocannabinol (Delta 9-THC), the principal component of cannabis, induces tachycardia in humans. In order to understand the impact of phytocannabinoids on human cardiovascular health, there is a need to study the metabolism of phytocannabinoids by cardiac cytochromes p450 (CYPs). CYP2J2, the primary CYP of cardiomyocytes, is responsible for the metabolism of the endocannabinoid, anandamide (AEA), into cardioprotective epoxides (EET-EAs). Herein, we have investigated the kinetics of the direct metabolism of six phytocannabinoids (Delta 9-THC, Delta 8-tetra-hydrocannabinol, cannabinol, cannabidiol, cannabigerol, and cannabichromene) by CYP2J2. CYP2J2 mainly produces 1'/1 ''-OH metabolites of these phytocannabinoids. These phytocannabinoids are metabolized with greater catalytic efficiency compared to the metabolism of AEA by CYP2J2. We have also determined that the phytocannabinoids are potent inhibitors of CYP2J2-mediated AEA metabolism, with Delta 9-THC being the strongest inhibitor. Most of the inhibition of CYP2J2 by the phytocannabinoids follow a noncompetitive inhibition model, and therefore dramatically reduce the formation of EET-EAs by CYP2J2. Taken together, these data demonstrate that phytocannabinoids are directly metabolized by CYP2J2 and inhibit human cardiac CYP2J2, leading to a reduction in the formation of cardioprotective EET-EAs.