REGULATION AND INHIBITION OF ARACHIDONIC ACID ω-HYDROXYLASES AND 20-HETE FORMATION

Abstract

▪ 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 ω-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 ω-hydroxylases, and the substrate selectivity and regulation of these enzymes has been the subject of numerous studies. Altered expression and function of arachidonic acid ω-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 ω-hydroxylases. This review discusses the substrate selectivity and expression of arachidonic acid ω-hydroxylases, regulation of these enzymes during disease, and the application of enzyme inhibitors to study 20-HETE function.