Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Faculty of Medicine, University of Toronto, 1 King's College Circle, M5S 1A8, Toronto, Ontario, Canada; Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, 8130, Tanta, Egypt.
Chem Biol Interact. 2019 Feb 1;299:140-150. doi: 10.1016/j.cbi.2018.12.004. Epub 2018 Dec 10.
Cytochrome P450 (P450) enzymes are superfamily of monooxygenases that hold the utmost diversity of substrate structures and catalytic reaction forms amongst all other enzymes. P450 enzymes metabolize arachidonic acid (AA) to a wide array of biologically active lipid mediators. P450-mediated AA metabolites have a significant role in normal physiological and pathophysiological conditions, hence they could be promising therapeutic targets in different disease states. P450 monooxygenases mediate the (ω-n)-hydroxylation reactions, which involve the introduction of a hydroxyl group to the carbon skeleton of AA, forming subterminal hydroxyeicosatetraenoic acids (HETEs). In the current review, we specified different P450 isozymes implicated in the formation of subterminal HETEs in varied tissues. In addition, we focused on the role of subterminal HETEs namely 19-HETE, 16-HETE, 17-HETE and 18-HETE in different organs, importantly the kidneys, heart, liver and brain. Furthermore, we highlighted their role in hypertension, acute coronary syndrome, diabetic retinopathy, non-alcoholic fatty liver disease, ischemic stroke as well as inflammatory diseases. Since each member of subterminal HETEs exist as R and S enantiomer, we addressed the issue of stereoselectivity related to the formation and differential effects of these enantiomers. In conclusion, elucidation of different roles of subterminal HETEs in normal and disease states leads to identification of novel therapeutic targets and development of new therapeutic modalities in different disease states.
细胞色素 P450（P450）酶是单加氧酶超家族，在所有其他酶中具有最多样的底物结构和催化反应形式。P450 酶将花生四烯酸（AA）代谢为广泛的生物活性脂质介质。P450 介导的 AA 代谢物在正常生理和病理生理条件下具有重要作用，因此它们可能是不同疾病状态下有前途的治疗靶点。P450 单加氧酶介导（ω-n）-羟化反应，其中涉及将羟基引入 AA 的碳骨架中，形成末端羟二十碳四烯酸（HETE）。在当前的综述中，我们指定了不同的 P450 同工酶参与不同组织中末端 HETE 的形成。此外，我们重点研究了末端 HETE 即 19-HETE、16-HETE、17-HETE 和 18-HETE 在不同器官中的作用，特别是肾脏、心脏、肝脏和大脑。此外，我们强调了它们在高血压、急性冠状动脉综合征、糖尿病视网膜病变、非酒精性脂肪性肝病、缺血性中风以及炎症性疾病中的作用。由于末端 HETE 的每个成员都存在 R 和 S 对映异构体，我们解决了与这些对映异构体的形成和差异效应相关的立体选择性问题。总之，阐明末端 HETE 在正常和疾病状态下的不同作用导致了在不同疾病状态下识别新的治疗靶点和开发新的治疗方法。
