Epoxygenase Pathways of Arachidonic Acid Metabolism (2001)

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 Y. Tsutsumi E. Sato T. Shimizu T. Abe K. Adv. Prostaglandin Thromboxane Leukotriene Res. 1995; 23: 211-213PubMed Google Scholar), inflammation (21Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1024) Google Scholar), hemostasis (22Node K. Ruan X.L. Dai J. Yang S.X. Graham L. Zeldin D.C. Liao J.K. J. Biol. Chem. 2001; 276: 15983-15989Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar), and a variety of intracellular signaling pathways (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, 23Burns K.D. Capdevila J. Wei S. Breyer M.D. Homma T. Harris R.C. Am. J. Physiol. 1995; 269: C831-C840Crossref PubMed Google Scholar, 24Chen J.K. Capdevila J. Harris R.C. J. Biol. Chem. 2000; 275: 13789-13792Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 25Dulin N.O. Alexander L.D. Harwalkar S. Falck J.R. Douglas J.G. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8098-8102Crossref PubMed Scopus (77) Google Scholar, 26Hoebel B.G. Graier W.F. Eur. J. Pharmacol. 1998; 346: 115-117Crossref PubMed Scopus (45) Google Scholar, 27Rzigalinski B.A. Willoughby K.A. Hoffman S.W. Falck J.R. Ellis E.F. J. Biol. Chem. 1999; 274: 175-182Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). This minireview will provide a general overview of the AA epoxygenase pathway with emphasis on the P450 enzymes involved in EET biosynthesis, the metabolic fate of the EETs once they are formed, and the biological relevance of the EETs in the kidney and cardiovascular system.Figure 2EET stereoisomers. Each of the four EET regioisomers can be biosynthesized as either the R,S or theS,R enantiomer.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Studies using purified and/or recombinant P450 enzymes have demonstrated that multiple P450s can metabolize AA to EETs, albeit with different catalytic efficiencies. Thus, members of the mammalian CYP1A, CYP2B, CYP2C, CYP2D, CYP2G, CYP2J, CYP2N, and CYP4A subfamilies have been shown to be capable of EET biosynthesis in vitro(28Rifkind A.B. Lee C. Chang T.K. Waxman D.J. Arch. Biochem. Biophys. 1995; 320: 380-389Crossref PubMed Scopus (219) Google Scholar, 29Keeney D.S. Skinner C. Wei S. Friedberg T. Waterman M.R. J. Biol. Chem. 1998; 273: 9279-9284Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 30Zeldin D.C. DuBois R.N. Falck J.R. Capdevila J.H. Arch. Biochem. Biophys. 1995; 322: 76-86Crossref PubMed Scopus (156) Google Scholar, 31Thompson C.M. Capdevila J.H. Strobel H.W. J. Pharmacol. Exp. Ther. 2000; 294: 1120-1130PubMed Google Scholar, 32Oleksiak M.F. Wu S. Parker C. Karchner S.I. Stegeman J.J. Zeldin D.C. J. Biol. Chem. 2000; 275: 2312-2321Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 33Nguyen X. Wang M.H. Reddy K.M. Falck J.R. Schwartzman M.L. Am. J. Physiol. 1999; 276: R1691-R1700PubMed Google Scholar, 34Wu S. Moomaw C.R. Tomer K.B. Falck J.R. Zeldin D.C. J. Biol. Chem. 1996; 271: 3460-3468Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 35Capdevila J.H. Karara A. Waxman D.J. Martin M.V. Falck J.R. Guengerich F.P. J. Biol. Chem. 1990; 265: 10865-10871Abstract Full Text PDF PubMed Google Scholar, 36Laethem R.M. Laethem C.L. Ding X. Koop D.R. J. Pharmacol. Exp. Ther. 1992; 262: 433-438PubMed Google Scholar). In general, the regioselectivity of EET formation is P450 isoform-specific. For example, CYP2C8 forms 14,15-EET and 11,12-EET in a ratio of 1.3:1.0 but does not produce significant amounts of 8,9-EET. In contrast, CYP2C9, which is >80% identical to CYP2C8, produces 14,15-EET, 11,12-EET, and 8,9-EET in a ratio of 2.3:1.0:0.5 (30Zeldin D.C. DuBois R.N. Falck J.R. Capdevila J.H. Arch. Biochem. Biophys. 1995; 322: 76-86Crossref PubMed Scopus (156) Google Scholar, 37Daikh B.E. Lasker J.M. Raucy J.L. Koop D.R. J. Pharmacol. Exp. Ther. 1994; 271: 1427-1433PubMed Google Scholar). The stereoselectivity of EET biosynthesis also depends on the P450 isoform involved in catalysis. Thus, CYP2C8 produces (14R,15S)-EET and (11R,12S)-EET with optical purities of 86 and 81%, respectively. In contrast, CYP2C9 produces (14R,15S)-EET and (11S,12R)-EETs with significantly lower optical purities (63 and 69%, respectively) (30Zeldin D.C. DuBois R.N. Falck J.R. Capdevila J.H. Arch. Biochem. Biophys. 1995; 322: 76-86Crossref PubMed Scopus (156) Google Scholar, 37Daikh B.E. Lasker J.M. Raucy J.L. Koop D.R. J. Pharmacol. Exp. Ther. 1994; 271: 1427-1433PubMed Google Scholar). Multiple P450s may contribute to EET biosynthesis in a given tissue or cell type. Moreover, the contribution of an individual P450 isoform will depend on both its organ/cellular abundance and its catalytic efficiency. For example, in human and rat liver, CYP2C isoforms are highly expressed and likely contribute significantly to EET biosynthesis. Indeed, polyclonal antibodies to CYP2C isoforms inhibit >70% of hepatic microsomal AA epoxygenase activity (37Daikh B.E. Lasker J.M. Raucy J.L. Koop D.R. J. Pharmacol. Exp. Ther. 1994; 271: 1427-1433PubMed Google Scholar, 38Zeldin D.C. Moomaw C.R. Jesse N. Tomer K.B. Beetham J. Hammock B.D. Wu S. Arch. Biochem. Biophys. 1996; 330: 87-96Crossref PubMed Scopus (129) Google Scholar, 39Capdevila J. Zeldin D.C. Karara A. Falck J.F. Adv. Mol. Cell Biol. 1996; 14: 317-339Crossref Scopus (9) Google Scholar). Similarly, in human and rat kidney, CYP2C isoforms are responsible for the majority of EET biosynthesis (30Zeldin D.C. DuBois R.N. Falck J.R. Capdevila J.H. Arch. Biochem. Biophys. 1995; 322: 76-86Crossref PubMed Scopus (156) Google Scholar, 40Holla V.R. Makita K. Zaphiropoulos P.G. Capdevila J.H. J. Clin. Invest. 1999; 104: 751-760Crossref PubMed Scopus (110) Google Scholar). In contrast, in human and rat heart, CYP2J isoforms are particularly abundant and have been proposed to be the predominant enzymes responsible for epoxidation of endogenous AA pools (34Wu S. Moomaw C.R. Tomer K.B. Falck J.R. Zeldin D.C. J. Biol. Chem. 1996; 271: 3460-3468Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar, 41Wu S. Chen W. Murphy E. Gabel S. Tomer K.B. Foley J. Steenbergen C. Falck J.R. Moomaw C.R. Zeldin D.C. J. Biol. Chem. 1997; 272: 12551-12559Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). Both CYP2J and CYP2C isoforms appear to contribute to EET biosynthesis in vascular endothelial cells, although their relative contribution remains unknown (21Node K. Huo Y. Ruan X. Yang B. Spiecker M. Ley K. Zeldin D.C. Liao J.K. Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1024) Google Scholar, 42Fisslthaler B. Popp R. Kiss L. Potente M. Harder D.R. Fleming I. Busse R. Nature. 1999; 401: 493-497Crossref PubMed Scopus (809) Google Scholar, 43Campbell W.B. Trends Pharmacol. Sci. 2000; 21: 125-127Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 44Zeldin D.C. Liao J.K. Trends Pharmacol. Sci. 2000; 21: 127-128Abstract Full Text Full Text PDF PubMed Google Scholar). In most tissues, however, the relative contribution of different P450s to EET biosynthesis remains unknown due to the absence of P450 isoform-specific chemical inhibitors and inhibitory antibodies. EET biosynthesis can be altered by factors that affect P450 expression and/or activity. Treatment of rats with phenobarbital induces CYP2B subfamily P450s leading to increased hepatic AA epoxygenase activity and altered regio- and stereochemical selectivity of rat liver EETs (35Capdevila J.H. Karara A. Waxman D.J. Martin M.V. Falck J.R. Guengerich F.P. J. Biol. Chem. 1990; 265: 10865-10871Abstract Full Text PDF PubMed Google Scholar, 45Karara A. Dishman E. Blair I. Falck J.R. Capdevila J.H. J. Biol. Chem. 1989; 264: 19822-19827Abstract Full Text PDF PubMed Google Scholar). In contrast, treatment of rats with the aromatic hydrocarbon β-naphthoflavone results in reduced hepatic AA epoxygenase activity and a concomitant increase in the formation of ω-terminal HETEs (35Capdevila J.H. Karara A. Waxman D.J. Martin M.V. Falck J.R. Guengerich F.P. J. Biol. Chem. 1990; 265: 10865-10871Abstract Full Text PDF PubMed Google Scholar). The effects of aromatic hydrocarbons on P450 epoxygenase activity are species-dependent. Treatment of fish and avian species with benzo(a)pyrene or 2,3,7,8-tetrachlorodibenzo-p-dioxin increases hepatic EET biosynthesis, likely by inducing CYP1A subfamily P450s (46Schlezinger J.J. Parker C. Zeldin D.C. Stegeman J.J. Arch. Biochem. 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Science. 1999; 285: 1276-1279Crossref PubMed Scopus (1024) Google Scholar, K. Ruan X.L. Dai J. Yang S.X. Graham L. Zeldin D.C. Liao J.K. J. Biol. Chem. 2001; 276: 15983-15989Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). that EETs in the in to their EETs have been shown to have effects on For example, 8,9-EET and produces a in the membrane T. M. E.F. J. Physiol. 1999; PubMed Scopus Google Scholar). J.R. T. P. M. Am. J. Physiol. 264: Google demonstrated that both and 11,12-EET significantly increase cell and intracellular L. J. Physiol. 1998; PubMed Scopus Google that 11,12-EET and intracellular in and that the P450 epoxygenase cell In contrast, have shown that 11,12-EET inhibitory effects on that EETs can either increase or activity on the metabolic and of the J. Capdevila J.H. Zeldin D.C. Mol. Pharmacol. 1999; PubMed Scopus Google Scholar). In an rat 11,12-EET significantly of S. Chen W. Murphy E. Gabel S. Tomer K.B. Foley J. Steenbergen C. Falck J.R. Moomaw C.R. Zeldin D.C. J. Biol. Chem. 1997; 272: 12551-12559Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar). the the of have to an of the and relevance of the AA epoxygenase a of important P450 isoforms are responsible for EET biosynthesis in are the signaling pathways and that the biological of the is the functional relevance of epoxygenase and are they with increased to human The of biological such as and/or the of P450 epoxygenase inhibitors and inhibitory and the of EET will that to and critical to R. B. and Capdevila for their the of for of