Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation.
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.
Kroetz
Deanna L
DL
Department of Biopharmaceutical Sciences, University of California, San Francisco, California 94143-2911, USA. deanna@itsa.ucsf.edu
Xu
Fengyun
F
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C409986:cytochrome P-450 omega-hydroxylase