Epoxygenase Pathways of Arachidonic Acid Metabolism

Abstract

arachidonic acid cis-epoxyeicosatrienoic acid dihydroxyeicosatrienoic acid hydroxyeicosatetraenoic acid soluble epoxide hydrolase prostaglandin H synthase lipoxygenase tetrahydrofuran phospholipid fatty acid-binding protein endothelial derived hyperpolarizing factor tissue plasminogen activator Arachidonic acid (AA)1 is present in vivo esterified to cell membrane glycerophospholipids. Activation of phospholipases (e.g. cytosolic phospholipase A2) releases free AA from the phospholipid (PL) pools and makes it available for oxidative metabolism by several enzyme systems (Fig. 1). The prostaglandin endoperoxide H synthases (PGHSs) metabolize AA to PGH2, which serves as the precursor of the prostaglandins, thromboxane and prostacyclin (1Smith W.L. Garavito R.M. DeWitt D.L. J. Biol. Chem. 1996; 271: 33157-33160Abstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar). The lipoxygenases (LOXs) convert AA to labile hydroperoxy intermediates that go on to form the leukotrienes, hydroxyeicosatetraenoic acids (HETEs) and lipoxins (2Brash A.R. J. Biol. Chem. 1999; 274: 23679-23682Abstract Full Text Full Text PDF PubMed Scopus (1155) Google Scholar). The PGHSs and LOXs have been extensively studied, and their eicosanoid products have been shown to play important functional roles in a variety of fundamental biological processes such as inflammation, cellular proliferation, and intracellular signaling (1Smith W.L. Garavito R.M. DeWitt D.L. J. Biol. Chem. 1996; 271: 33157-33160Abstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar, 2Brash A.R. J. Biol. Chem. 1999; 274: 23679-23682Abstract Full Text Full Text PDF PubMed Scopus (1155) Google Scholar). In contrast, less is known about the “third pathway” of AA metabolism wherein multiple cytochromes P450 metabolize AA to three types of eicosanoid products (3Capdevila J.H. Falck J.R. Harris R.C. J. Lipid Res. 2000; 41: 163-181Abstract Full Text Full Text PDF PubMed Google Scholar, 4Oliw E.H. Prog. Lipid Res. 1994; 33: 329-354Crossref PubMed Scopus (139) Google Scholar, 5Makita K. Falck J.R. Capdevila J.H. FASEB J. 1996; 10: 1456-1463Crossref PubMed Scopus (120) Google Scholar, 6McGiff J.C. Quilley J. Curr. Opin. Nephrol. Hypertens. 2001; 10: 231-237Crossref PubMed Scopus (86) Google Scholar). Allylic oxidation forms several midchain conjugated dienols (5-, 8-, 9-, 11-, 12-, and 15-HETEs). ω-terminal hydroxylation forms C16–C20 alcohols of AA (16-, 17-, 18-, 19-, and 20-HETEs). Olefin epoxidation (also called the epoxygenase reaction) results in the production of fourcis-epoxyeicosatrienoic acids (14,15-, 11,12-, 8,9-, and 5,6-EETs), each of which can be formed as either the R,S or the S,R enantiomer (Fig. 2). Studies have demonstrated that P450 epoxygenase-derived eicosanoids have a multitude of potent biological activities. For example, EETs have been shown to have potent effects on peptide hormone secretion (7Cashman J.R. Hanks D. Weiner R.I. Neuroendocrinology. 1987; 46: 246-251Crossref PubMed Scopus (48) Google Scholar, 8Falck J.R. Manna S. Moltz J. Chacos N. Capdevila J. Biochem. Biophys. Res. Commun. 1983; 114: 743-749Crossref PubMed Scopus (147) Google Scholar, 9Snyder G.D. Yadagiri P. Falck J.R. Am. J. Physiol. 1989; 256: E221-E226PubMed Google Scholar), vascular and bronchial smooth muscle tone (10Campbell W.B. Gebremedhin D. Pratt P.F. Harder D.R. Circ. Res. 1996; 78: 415-423Crossref PubMed Scopus (1115) Google Scholar, 11Proctor K.G. Falck J.R. Capdevila J. Circ. Res. 1987; 60: 50-59Crossref PubMed Scopus (153) Google Scholar, 12Zou A.P. Fleming J.T. Falck J.R. Jacobs E.R. Gebremedhin D. Harder D.R. Roman R.J. Am. J. Physiol. 1996; 270: F822-F832PubMed Google Scholar, 13Zhu D. Bousamra M. Zeldin D.C. Falck J.R. Townsley M. Harder D.R. Roman R.J. Jacobs E.R. Am. J. Physiol. 2000; 278: L335-L343PubMed Google Scholar, 14Harder D.R. Campbell W.B. Roman R.J. J. Vasc. Res. 1995; 32: 79-92Crossref PubMed Scopus (279) Google Scholar, 15Zeldin D.C. Plitman J.D. Kobayashi J. Miller R.F. Snapper J.R. Falck J.R. Szarek J.L. Philpot R.M. Capdevila J.H. J. Clin. Invest. 1995; 95: 2150-2160Crossref PubMed Scopus (105) Google Scholar), and ionic transport (16Harris R.C. Homma T. Jacobson H.R. Capdevila J. J. Cell. Physiol. 1990; 144: 429-437Crossref PubMed Scopus (92) Google Scholar, 17Romero M.F. Madhun Z.T. Hopfer U. Douglas J.G. Adv. Prostaglandin Thromboxane Leukotriene Res. 1991; 21A: 205-208PubMed Google Scholar, 18Pascual J.M. McKenzie A. Yankaskas J.R. Falck J.R. Zeldin D.C. J. Pharmacol. Exp. Ther. 1998; 286: 772-779PubMed Google Scholar). The EETs have also been shown to play critical roles in regulating cellular proliferation (16Harris R.C. Homma T. Jacobson H.R. Capdevila J. J. Cell. Physiol. 1990; 144: 429-437Crossref PubMed Scopus (92) Google Scholar, 19Chen J.K. Falck J.R. Reddy K.M. Capdevila J. Harris R.C. J. Biol. Chem. 1998; 273: 29254-29261Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 20Sheu H.L. Omata K. Utsumi