Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation

Annu Rev Pharmacol Toxicol. 2005;45:413-38. doi: 10.1146/annurev.pharmtox.45.120403.100045.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxyeicosatetraenoic Acids / metabolism*
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • Mixed Function Oxygenases / metabolism*

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Cytochrome P-450 Enzyme System
  • Mixed Function Oxygenases
  • cytochrome P-450 omega-hydroxylase