Arachidonate epoxygenase / epoxide hydrolase

The cytochrome P450-dependent formation of polyunsaturated fatty acid epoxides is an important biochemical pathway creating mediators of inflammation and blood pressure regulation. Once formed these compounds can be incorperated into phospholipid membrance, and released by the action of phospholipase A2. The epoxides of arachidonic acid, i.e. the epoxyeicosatrieneoic acid or EETs, are putative endothelial derived hyperpolarization factors which increase the open state probability of Ca++ sensitive K+ channels, leading to vasodilation in arteriolar beds. The 11(12)-EET in particular appears to have potent functions in vasodilation, and are inhibitors of NFKb dependent inflammatory signalling, and PAI-1 activity. The 5(6)-EET appears unique, in that its metabolic transformation through cyclooxygenase activities produces potent vasoconstrictors. With the exception of the 5(6)-EET, these epoxy fatty acids are good substrates for the soluble epoxide hydrolase. Hydrolytic tranformation to vicinal diols eliminates vasoactive actions, however these vicinal diols have been reported to have other biological activites, including PPAR-alpha activation. Recent development of inhibitors of the soluble epoxide hydrolase are proving to have potent anti-inflammatory, anti-hypertensive, and anti-nociceptive properties. Reports of enzyme catalyzed glutathione-conjugates of the epoxy fatty acids have been reported, but the activity and relavance of these potential metabolic products are unknown to date.

黄素P450依赖性多不饱和脂肪酸环氧化反应是一条至关重要的生化途径，该途径生成炎症和血压调节的介质。一旦形成，这些化合物可被整合入磷脂质膜中，并在磷脂酶A2的作用下释放。花生四烯酸的环氧化合物，即环氧二十碳三烯酸或EETs，被认为是内皮来源的超极化因子，它们能够增加钙离子敏感的钾通道开放状态的几率，从而导致动脉床血管舒张。特别是11(12)-EET在血管舒张中具有显著的生理功能，并且是NFKb依赖性炎症信号传导和PAI-1活性的抑制剂。5(6)-EET则表现出其独特的特性，其通过环氧化酶活性进行的代谢转化产生了强效的血管收缩剂。除了5(6)-EET之外，这些环氧脂肪酸是可溶性环氧水解酶的良好底物。通过水解转化生成的邻二醇消除了血管活性作用，然而，这些邻二醇已被报道具有其他生物学活性，包括PPAR-α的激活。近期，可溶性环氧水解酶抑制剂的研发显示出强大的抗炎、抗高血压和镇痛特性。关于环氧脂肪酸的酶催化谷胱甘肽结合物的报道已有所闻，但这些潜在代谢产物的活性和相关性至今尚未明了。