Kroetz Deanna L, Xu Fengyun
Department of Biopharmaceutical Sciences, University of California, San Francisco, California 94143-2911, USA.
Annu Rev Pharmacol Toxicol. 2005;45:413-38. doi: 10.1146/annurev.pharmtox.45.120403.100045.
Cytochrome P450-catalyzed metabolism of arachidonic acid is an important pathway for the formation of paracrine and autocrine mediators of numerous biological effects. The omega-hydroxylation of arachidonic acid generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in numerous tissues, particularly the vasculature and kidney tubules. Members of the cytochrome P450 4A and 4F families are the major omega-hydroxylases, and the substrate selectivity and regulation of these enzymes has been the subject of numerous studies. Altered expression and function of arachidonic acid omega-hydroxylases in models of hypertension, diabetes, inflammation, and pregnancy suggest that 20-HETE may be involved in the pathogenesis of these diseases. Our understanding of the biological significance of 20-HETE has been greatly aided by the development and characterization of selective and potent inhibitors of the arachidonic acid omega-hydroxylases. This review discusses the substrate selectivity and expression of arachidonic acid omega-hydroxylases, regulation of these enzymes during disease, and the application of enzyme inhibitors to study 20-HETE function.
细胞色素P450催化的花生四烯酸代谢是众多生物效应旁分泌和自分泌介质形成的重要途径。花生四烯酸的ω-羟化在众多组织中，特别是在脉管系统和肾小管中产生大量的20-羟基二十碳四烯酸（20-HETE）。细胞色素P450 4A和4F家族成员是主要的ω-羟化酶，并且这些酶的底物选择性和调节一直是众多研究的主题。在高血压、糖尿病、炎症和妊娠模型中，花生四烯酸ω-羟化酶的表达和功能改变表明20-HETE可能参与这些疾病的发病机制。花生四烯酸ω-羟化酶选择性强效抑制剂的开发和特性极大地帮助了我们对20-HETE生物学意义的理解。本综述讨论了花生四烯酸ω-羟化酶的底物选择性和表达、疾病期间这些酶的调节以及酶抑制剂在研究20-HETE功能中的应用。
