Abstract
Cytochrome P450 (CYP450) epoxygenase enzymes demonstrate organ and cell specific expression and each CYP450 enzyme isoform produces a distinct pattern of epoxyeicosatrienoic acids (EETs). Investigations are beginning to describe the regulation of specific tissue CYP450 epoxygenase isoforms that may be associated with alterations in organ function that occur during various physiological and pathophysiological states. The main biological actions of EETs are their ability to affect epithelial ion transport and vascular smooth muscle cell function. This chapter focuses on the organ localization and production of EETs and the action of EETs on epithelial and vascular smooth muscle cells.
Similar content being viewed by others
References
Capdevila, J. H., Falck, J. R., and Estabrook, R. W. (1992) Cytochrome P450, and arachidonate cascade. FASEB J. 6, 731–736.
Capdevila, J., Chacos, N., Werringloer, J., Prough, R. A., and Estabrook, R. W. (1981) Liver microsomal cytochrome P450, and the oxidative metabolism of arachidonic acid. Proc. Nat. Acad. Sci. USA 78, 5362–5366.
Makita, K., Falck, J. R., and Capdevila, J. H. (1996) Cytochrome P450, the arachidonic acid cascade, and hypertension, new vistas for an old system. FASEB J. 10, 1456–1463.
Morrison, A. R. and Pascoe, N. (1981) Metabolism of arachidonate through NADPH-dependent oxygenase of renal cortex. Proc. Nat. Acad. Sci. USA 78, 7375–7378.
Daikh, B. E., Laethem, R. M., and Koop, D. R. (1994) Stereoselective epoxidation of arachidonic acid by cytochrome P-450s 2CAA, and 2C2. J. Pharmacol. Exp. Ther. 269, 1130–1135.
Rifkind, A. B., Lee, C., Chang, T. K. H., and Waxman, D. J. (1995) Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2, Regioselective oxygenation, and evidence for a role for CYP2C enzymes in arachidonic epoxygenation in human liver microsomes. Arch. Biochem. Biophys. 320, 380–389.
Zeldin, D. C., Moomaw, C. R., Jesse, N., Tomer, K. B., Beetham, J., Hammock, B. D., and Wu, S. (1996) Biochemical characterization of the human liver cytochrome P450 arachidonic acid epoxygenase pathway. Arch. Biochem. Biophys. 330, 87–96.
Oliw, E. H. and Oates, J. A. (1981) Oxygenation of arachidonic acid by hepatic microsomes of the rabbit, mechanism of synthesis of two vicinal diols. Biochem. et Biophys. Acta 666, 327–340.
Luo, G., Zeldin, D. C., Blaisdell, J. A., Hodgson, E., and Goldstein, J. A. (1998) Cloning, and expression of murine CYP2Cs, and their ability to metabolize arachidonic acid. Arch. Biochem. Biophys. 357, 45–57.
Sewer, M. B., and Morgan, E. T. (1997) Nitric oxide-dependent suppression of P450 2C11 expression by interleukin-1b and endotoxin in primary rat hepatocytes. Biochem. Pharmacol. 54, 729–737.
Zeldin, D. C., DuBois, R. N., Falck, J. R., and Capdevila, J. H. (1995) Molecular cloning, expression, and characterization of an endogenous human cytochrome P450 arachidonic acid epoxygenase isoform. Arch. Biochem. Biophys. 322, 76–86.
Daikh, B. E., Lasker, J. M., Raucy, J. L., and Koop, D. R. (1997) Regio-, and stereoselective epoxidation of arachidonic acid by human cytochromes P450 2C8, and 2C9. J. Pharmacol. Exp. Ther. 271, 1427–1433.
Merrill, A. H., Nikolova-Karakashian, M., Schmelz, E. M., Morgan, E. T., and Stewart, J. (1999) Regulation of cytochrome P450 expression by sphingolipids. Chem. Phys. Lipids 102, 131–139.
Shiba D. and Shimamoto N. (1999) Attenuation of endogenous oxidative stress-induced cell death by cytochrome P450 inhibitors in primary cultures of rat hepatocytes. Free Radical Biol. Med. 27, 1019–1026.
Sewer, M. B., Koop, D. R., and Morgan, E. T. (1997) Differential inductive, and suppressive effects of endotoxin, and particulate irritants on hepatic, and renal cytochrome P-450 expression. J. Pharmacol. Exp. Ther. 280, 1445–1454.
Iber, H., Chen, Q., Sewer, M., and Morgan, E. T. (1997) Regulation of hepatic cytochrome P450 2C11 by glucocorticoids. Arch. Biochem. Biophys. 345, 305–310.
Sewer, M. B., Barclay, T. B., and Morgan, E. T. (1998) Down-regulation of cytochrome P450 mRNAs, and proteins in mice lacking a functional NOS2 gene. Mol. Pharmacol. 54, 273–279.
Qu, W., Rippe, R. A., Ma, J., Scarborough, P., Biagini, C., Fiedorek, F. T., Travlos, G. S., Parker, C., and Zeldin, D. C. (1998) Nutritional status modulates rat liver cytochrome P450 arachidonic acid metabolism. Mol. Pharmacol. 54, 504–513.
Irizar, A., Barnett, C. R., Flatt, P. R., and Ioannides, C. (1995) Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat. Eur. J. Pharmacol. 293, 385–393.
Yoshida, S., Hirai, A., Tamura, Y., and Yoshida, S. (1990) Possible involvement of arachidonic acid metabolites of cytochrome P450 monooxygenase pathway in vasopressin-stimulated glycogenolysis in isolated rat hepatocytes. Arch. Biochem. Biophys. 280, 346–351.
Falck, J. R., Manna, S., Moltz, J., Chacos, N., and Capdevila, J. (1983) Epoxyeicosatrienoic acids stimulate glucagon, and insulin release from isolated rat pancreatic islets. Biochem. Biophys. Res. Comm. 114, 743–749.
Karara, A., Dishman, E., Jacobson, H., Falck, J. R., and Capdevila, J. H. (1990) Arachidonic acid epoxygenase, Stereochemical analysis of the endogenous epoxyeicosatrienoic acids of human kidney cortex. FEBS Letters 268, 227–230.
Karara, A., Makita, K., Jacobson, H. R., Falck, J. R., Guengerich, F. P., DuBois, R. N., and Capdevila, J. H. (1993) Molecular cloning, expression, and enzymatic characterization of the rat kidney cytochrome P-450 arachidonic acid epoxygenases. J. Biol. Chem. 268, 13,565–13,570.
Wang, M. H., Stec, D. E., Balazy, M., Mastyugin, V., Yang, C. S., Roman, R. J., and Schwartzman, M. L. (1996) Cloning, sequencing, and cDNA-directed expression of the rat renal CYP4A2, arachidonic acid w-hydroxylation, and 11, 12-epoxidation by CYP4A2. Arch. Biochem. Biophys. 336, 240–250.
Imig, J. D., Zou, A. P., Stec, D. E., Harder, D. R., Falck, J. R., and Roman, R. J. (1996) Formation, and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles. Am. J. Physiol. 270, R217-R227.
Ma, J., Qu, W., Scarborough, P. E., Tomer, K. B., Moomaw, C. R., Maronpot, R., Davis, L. S., Breyer, M. D., and Zeldin, D. C. (1999) Molecular cloning, enzymatic characterization, developmental expression, and cellular localization of a mouse cytochrome P450 highly expressed in kidney. J. Biol. Chem. 274, 17,777–17,788.
Takahashi, K., Harris, R. C., Capdevila, J. H., Karara, A., Makita, K., Jacobson, H. R., Munger, K. A., and Badr, K. F. (1993) Induction of renal arachidonate cytochrome P-450 epoxygenase after uninephrectomy, counterregulation of hyperfiltration. J. Am. Soc. Nephrol. 3, 1496–1500.
Reyes, A. A. and Klahr, S. (1992) Cytochrome P-450 pathway in renal function of normal rats, and rats with bilateral uretral obstruction. Proc. Soc. Exp. Biol. Med. 201, 278–283.
Tamura, Y., Imaoka, S., Gemba, M., and Funae, Y. (1997) Effects of ischemia-reperfusion on individual cytochrome P450 isoforms in the rat kidney. Life Sci. 60, 143–149.
Makita, K., Takahashi, K., Karara, A., Jacobson, H. R., Falck, J. R., and Capdevila, J. H. (1994) Experimental, and/or genetically controlled alterations of the renal microsomal cytochrome P450 epoxygenase induce hypertension in rats fed a high salt diet. J. Clin. Invest. 94, 2414–2420.
Capdevila, J. H., Wei, S., Yan, J., Karara, A., Jacobson, H. R., Falck, J. R., Guengerich, F. P., and DuBois, R. N. (1992) Cytochrome P-450 arachidonic acid epoxygenase, Regulatory control of the renal epoxygenase by dietary salt loading. J. Biol. Chem. 267, 21,720–21,726.
Rahman, M., Wright, J. T., and Douglas, J. G. (1997) The role of the cytochrome P450-dependent metabolites of arachidonic acid in blood pressure regulation, and renal function. Am. J. Hypertens. 10, 356–365.
Messer-Letienne, I., Bernard, N., Benzoni, D., and Sassard, J. (1998) Cytochrome P-450-dependent arachidonate metabolites, and renal functions in the Lyon hypertensive rat. Cli. Exp. Pharmacol. Physiol. 25, 559–563.
Monneret G., Sassard J., and Benzoni D. (1999) Renal effects of cP450 arachidonate metabolites in the Lyon hypertensive rat. Fundam. Clin. Pharmacol. 13, 226–231.
Wu, S., Moomaw, C. R., Tomer, K. B., Falck, J. R., and Zeldin, D. C. (1996) Molecular cloning, and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart. J. Biol. Chem. 271, 3460–3468.
Wu, S., Chen, W., Murphy, E., Gabel, S., Tomer, K. B., Foley, J., Steenbergen, C., Falck, J. R., Moomaw, C. R., and Zeldin, D. C. (1997) Molecular cloning, expression, and functional significance of a cytochrome P450 highly expressed in rat heart myocytes. J. Biol. Chem. 272, 12,551–12,559.
Hasunuma, K., Terano, T., Tamura, Y., and Yoshida, S. (1991) Formation of epoxyeicosatrienoic acids from arachidonic acid by cultured rat aortic smooth muscle cell microsomes. Prostaglandins Leukotrienes, and Essential Fatty Acids 42, 171–175.
Rosolowsky, M. and Campbell, W. B. (1993) Role of PGI2, and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid. Am. J. Physiol. 264, H327-H335.
VanRollins, M., Kaduce, T. L., Knapp, H. R., and Spector, A. A. (1993) 14, 15-Epoxyeicosatrienoic acid metabolism in endothelial cells. J. Lip. Res. 34, 1931–1942.
Rosolowsky, M. and Campbell, W. B. (1996) Synthesis of hydroxeicosatetraenoic (HETEs), and epoxyeicosatrienoic acids (EETs) by cultured bovine coronary artery endothelial cells. Biochem. et Biophys. Acta 1299, 267–277.
Campbell, W. B, Gebremedhin, D., Pratt, P. F., and Harder, D. R. (1996) Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ. Res. 78, 415–423.
Harder, D. R., Campbell, W. B., and Roman, R. J. (1995) Role of cytochrome P-450 enzymes, and metabolites of arachidonic acid in the control of vascular tone. J. Vas. Res. 32, 79–92.
Harder, D. R., Lange, A. R., Gebremedhin, D., Birks, E. K., and Roman, R. J. (1997) Cytochrome P450 metabolites of arachidonic acid as intracellular signaling molecules in vascular tissue. J. Vas. Res. 34, 237–243.
Fulton, D., Balazy, M., McGiff, J. C., and Quilley, J. (1997) Possible contribution of platelet cyclooxygenase to the renal vascular action of 5,6-epoxyeicosatrienoic acid. J. Pharmacol. Exp. Ther. 277, 1195–1199.
Zhu Y., Schieber, E. B., McGiff, J. C., and Balazy, M. (1995) Identification of arachidonate P-450 metabolites in human platelet phospholipids. Hypertension 25, 854–859.
Balazy, M. (1991) Metabolism of 5, 6-epoxyeicosatrienoic acid by human platelet, formation of novel thromboxane analogs. J. Biol. Chem. 266, 23,561–23,567.
Fang, X., Kaduce, T. L., Weintraub, N. L., and Spector, A. A. (1997) Cytochrome P450 metabolites of arachidonic acid, rapid incorporation, and hydration of 14, 15-epoxyeiocosatrienoic acid in arterial smooth muscle cells. Prostaglandins Leukotrienes, and Essential Fatty Acids 57, 367–371.
VanRollins, M., Kaduce, T. L., Fang, X., Knapp, H. R., and Spector, A. A. (1996) Arachidonic acid diols produced by cytochrome P-450 monooxygenases are incorporated into phospholipids of vascular endothelial cells. J. Biol. Chem. 271, 14,001–14,009.
Weintraub, N. L., Fang, X., Kaduce, T. L., VanRollins, M., Chatterjee, P., and Spector, A. A. (1999) Epoxide hydrolases regulate epoxyeicosatrienoic acid incorporation into coronary endothelial phospholipids. Am. J. Physiol. 277, H2098-H2108.
Malcolm, K. C. and Fitzgerald, F. A. (1992) Epoxyeicosatrienoic acids inhibit Ca2+ entry into platelets stimulated by thapsigargin, and thrombin. J. Biol. Chem. 267, 19,854–19,858.
Rosolowsky, M., Falck, J. R., Willerson, J. T., and Campbell, W. B. (1990) Synthesis of lipoxygenase, and epoxygenase products of arachidonic acid by normal, and stenosed canine coronary arteries. Circ. Res. 66, 608–621.
Node, K., Huo, Y., Ruan, X., Yang, B., Spieker, M., Ley, K., Zeldin, D. C., and Liao, J. K. (1999) Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285, 1276–1279.
Sheu, H. L., Omata, K., Utsumi, Y., Tsutsumi, E., Sato, T., Shimizu, T., and Abe, K. (1995) Epoxyeicosatrienoic acids stimulate the growth of vascular smooth muscle cells. Adv. Prostaglandin, Thromboxane, and Leukotriene Res. 23, 211–213.
Lee, H. C., Lu, T., Weintraub, N. L., VanRollins, M., Spector, A. A., and Shibata, E. F. (1999) Effects of epoxyeicosatrienoic acids on the cardiac sodium channels in isolated rat ventricular myocytes. J. Physiol. 519, 153–168.
Moffat, M. P., Ward, C. A., Bend, J. R., Mock, T., Farhangkhoee, P., and Karmazyn, M. (1993) Effects of epoxyeicosatrienoic acids on isolated hearts, and ventricular myocytes. Am. J. Physiol. 264, H1154-H1160.
Zeldin, D. C., Foley, J., Ma, J., Boyle, J. E., Pascual, J. M. S., Moomaw, C. R., Tomer, K. B., Steenbergen, C., and Wu, S. (1997) CYP2J subfamily of P450s in the lung, expression, localization, and potential functional significance. Mol. Pharmacol. 50, 1111–1117.
Knickle, L. C. and Bend, J. R. (1994) Bioactivation of arachidonic acid by the cytochrome P450 monooxygenases of guinea pig lung the orthologue of cytochrome P450 2 B4 is solely responsible for formation of epoxyeicosatrienoic acids. Mol. Pharmacol. 45, 1273–1280.
Zhu, D., Bousamra, M., Zeldin, D. C., Falck J. R., Townsley, M. I., Harder, D. R., Roman, R. J., and Jacobs, E. R. (2000) Epoxyeicosatrienoic acids constrict isolated pressurized rabbit pulmonary arteries. Am. J. Physiol. 278, L335-L343.
Zeldin, D. C., Plitman, J. D., Kobayashi, J., Miller, R. F., Snapper, J. R., Falck J. R., Szarek, J. L., Philpot, R. M., and Capdevila, J. H. (1995) The rabbit pulmonary cytochrome P450 arachidonic acid metabolic pathway, characterization, and significance. J. Clin. Invest. 95, 2150–2160.
Amruthesh, S. C., Falck, J. R., and Ellis, E. F. (1992) Brain synthesis, and cerebrovascular action of epoxygenase metabolites of arachidonic acid. J. Neurochem. 58, 503–510.
Alkayed, N. J., Narayanan, J., Gebremedhin, D., Medhora, M., Roman, R. J., and Harder, D. R. (1996) Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes. Stroke 27, 971–979.
Gebremedhin, D., Ma, Y. H., Falck, J. R., Roman, R. J., VanRollins, M., and Harder, D. R. (1992) Mechanism of action of cerebral epoxyeicosatrienoic acids on cerebral arterial smooth muscle. Am. J. Physiol. 263, H519-H525.
Farin, F. M. and Omiecinski, C. J. (1993) Regiospecific expression of cytochrome P450s, and microsomal epoxide hydrolase in human brain tissue. J. Toxicol. Environ. Health 40, 317–335.
Schilter, B. and Omiecinski, C. J. (1993) Regional distribution, and expression modulation of cytochrome P-450, and epoxide hydrolase mRNAs in the rat brain. Mol. Pharmacol. 44, 990–996.
Medhora, M. and Harder, D. R. (1998) Functional role of epoxyeicosatrienoic acids, and their production in astrocytes, approaches for gene transfer, and therapy. Int. J. Mol. Med. 6, 661–669.
Alkayed, N. J., Birks, E. K., Narayanan, J., Petrie, K. A., Kohler-Cabot, A. E., and Harder, D. R. (1997) Role of P-450 arachidonic acid epoxygenase in the response of cerebral blood flow to glutamate in rats. Stroke 28, 1066–1072.
Kozak, W., Archuleta, I., Mayfield, K. P., Kozak, A., Rudolph, K., and Kluger, M. J. (1998) Inhibitors of alternative pathways of arachidonate metabolism differentially affect fever in mice. Am. J. Physiol. 275, R1031-R1040.
Koike, K., Kusunose, E., Nishikawa, Y., Ichihara, K., Inagaki, S., Takagi, H., Kikuta, Y., and Kusunose, M. (1997) Purification, and characterization of rabbit small intestinal cytochromes P450 belonging to CYP2J, and CYP4A subfamilies. Biochem. & Biophys. Res. Comm. 232, 643–647.
Zeldin, D. C., Foley, J., Goldsworthy, S. M., Cook, M. E., Boyle, J. E., Ma, J., Moomaw, C. R., Tomer, K. B., Steenbergen, C., and Wu, S. (1997) CYP2J subfamily cytochrome P450s in the gastrointestinal tract, expression, localization, and potential functional significance. Mol. Pharmacol. 51, 931–943.
Zhang, Q. Y., Ding, X., and Kaminisky, L. S. (1997) cDNA cloning, heterologous expression, and characterization of rat intestinal CYP2J4. Arch. Biochem. Biophys. 340, 270–278.
Gonzalez, E., Jawerbaum, A., Novaro, V., and Gimeno, M. A. F. (1997) Influence of epoxyeicosatrienoic acids on uterine function. Prostaglandins Leukotrienes, and Essential Fatty Acids 56, 57–61.
Schaefer, W. R., Werner, K., Schweer, H., Schneider, J., Arbogast, E., and Zahradnik, H. P. (1997) Cytochrome P450 metabolites of arachidonic acid in human placenta. Prostaglandins 54, 677–687.
Zosmer, A., Rendell, N. B., Taylor, G. W., Elder, M. G., and Sullivan, M. H. F. (1995) Formation, and metabolism of 14, 15-epoxyeicosatrienoic acid by human reproductive tissues. Biochem. et Biophys. Acta 1258, 234–240.
Zeldin, D. C., Foley, J., Boyle, J. E., Moomaw, C. R., Tomer, K. B., Parker, C., Steenbergen, C., and Wu, S. (1997) Predominant expression of an arachidonate epoxygenase in islets of Langerhans cells in human, and rat pancreas. Endocrinology 138, 1338–1346.
Keeney, D. S., Skinner, C., Wei, S., Friedberg, T., and Waterman, M. R. (1998) A keratinocyte-specific epoxygenase, CYP2B12, metabolizes arachidonic acid with unusual selectivity, producing a single major epoxyeicosatrienoic acid. J. Biol. Chem. 273, 9279–9284.
Fang, X., Kaduce, T. L., VanRollins, M., Weintraub, N. L., and Spector, A. A. (2000) Conversion of epoxyeicosatrienoic acids (EETs) to chain-shortened epoxy fatty acids by human skin fibroblasts. J. Lip. Res. 41, 66–74.
Jacobson, H. R., Corona, S., Capdevila, J. H., Chacos, N., Manna, S., Womack, A., and Falck, J. R. (1985) Effects of epoxyeicosatrienoic acids on ion transport in the rabbit cortical collecting tubule, in Prostaglandins, and Membrane Ion Transport. (Braquet, P., Garay, R. P., Frohlich, J. C., and Nicosia, S., eds.), Raven Press, New York, pp. 311–318.
Sakairi, Y., Jacobson, H. R., Noland, T. D., Capdevila, J. H., Falck, J. R., and Breyer, M. D. (1995) 5, 6-EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis. Am. J. Physiol. 268, F931-F939.
Satoh, T., Cohen, H. T., and Katz, A. I. (1993) Intracellular signaling in the regulation of renal Na-K-ATPase, role of eicosanoids. J. Clin. Invest. 91, 409–415.
Silverstein, D. M., Barac-Nieto, M., and Spitzer, A. (1999) Multiple arachidonic acid metabolites inhibit sodium-dependent phosphate transport in OK cells. Prostaglandins Leukotrienes, and Essential Fatty Acids 61, 165–169.
Chen, J. K., Falck, J. R., Reddy, K. M., Capdevilla, J., and Harris, R. C. (1998) Epoxyeicosatrienoic acids, and their sulfonimide derivatives stimulate tyrosine phosphorylation, and induce mitogenesis in renal epithelial cells. J. Biol. Chem. 273, 29,254–29,261.
Schlondorff, D., Petty, E., Oates, J. A., Jacoby, M., and Levine, S. D. (1987) Epoxygenase metabolites of arachidonic acid inhibit vasopressin response in toad bladder. Am. J. Physiol. 253, F464-F470.
Hirt, D. L., Capdevila, J. H., Falck, J. R., Breyer, M. D., and Jacobson, H. R. (1989) Cytochrome P450 metabolites of arachidonic acid are potent inhibitors of vasopressin action on rabbit cortical collecting duct. J. Clin. Invest. 84, 1805–1812.
Dulin, N. O., Alexander, L. D., Harwalkar, S., Falck, J. R., and Douglas, J. G. (1999) Phospholipase A2-mediated activation of mitogen-activated protein kinase by angiotensin II. Proc. Natl. Acad. Sci. USA 95, 8098–8102.
Madhun, Z. T., Goldthwait, D. A., McKay, D., Hopfer, U., and Douglas, J. G. (1991) An epoxygenase metabolite of arachidonic acid mediates angiotensin II-induced rises in cytosolic calcium in rabbit proximal tubule epithelial cells. J. Clin. Invest. 88, 456–461.
Romero, M. F., Madhun, Z. T., Hopfer, U., and Douglas, J. G. (1991) An epoxygenase metabolite of arachidonic acid 5, 6-epoxyeicosatrienoic acid mediates angiotensin-induced natriuresis in proximal tubular epithelium. Adv. Prostaglandin, Thromboxane, and Leukotriene Res. 21, 205–208.
Burns, K. D., Capdevila, J., Wei, S., Breyer, M. D., Homma, T., and Harris, R. C. (1995) Role of cytochrome P-450 epoxygenase metabolites in EGF signaling in renal proximal tubule. Am. J. Physiol. 269, C831-C840.
Grahm-Lorence, S., Truan, G., Peterson, J. A., Falck, J. R., Wei, S., Helvig, C., and Capdevila, J. (1997) An active site substitution, F87V, converts cytochrome P450 BM-3 into a regio-, and stereoselective (14S, 15R)- arachidonic acid epoxygenase. J. Biol. Chem. 272, 1127–1135.
Chen, J. K., Wang, D. W., Falck J. R., Capdevila, J., and Harris, R. C. (1999) Transfection of an active cytochrome P450 arachidonic acid epoxygenase indicates that 14, 15-epoxyeicosatrienoic acid functions as an intracellular second messenger in response to epidermal growth factor. The J. Biol. Chem. 274, 4764–4769.
Douglas, J. G., Romero, M., and Hopfer, U. (1990) Signaling mechanisms coupled to angiotensin receptor of proximal tubular epithelium. Kid. Int. 30, S43-S47.
Peri, K. G., Almazan, G., Varma, D. R., and Chemtob, S. (1998) A role for protein kinase C in stimulation of prostaglandin G/H synthase-2 transcription by 14, 15-epoyeicosatrienoic acid. Biochem. Biophys. Res. Comm. 244, 96–101.
Peri, K. G., Varma, D. R., and Chemtob, S. (1997) Stimulation of prostaglandin G/H synthase-2 expression by arachidonic acid monoxygenase product, 14, 15-epoxyeicosatrienoic acid. FEBS Letters 416, 269–272.
Pascual, J. M. S., McKenzie, A., Yankaskas, J. R., Falck J. R., and Zeldin, D. C. (1998) Epoxygenase metabolites of arachidonic acid affect electrophysiologic properties of rat tracheal epithelial cells. J. Pharmacol. Exp. Ther. 286, 772–779.
Kersting, U. and Spring, K. R. (1996) Ketoconazole activates chloride, and fluid secretion by necturus gallbladder at low pH. J. Am. Soc. Nephrol. 7, 254–259.
Salvail, D., Dumoulin, M., and Rousseau, E. (1998) Direct modulation of tracheal C1−-channel activity by 5, 6-, and 11, 12-EET. Am. J. Physiol. 275, L432-L441.
Dumoulin, M., Salvail, D., Gaudreault, S. B., Cadieux, A., and Rousseau, E. (1998) Epoxyeicosatrienoic acids relax airway smooth muscles, and directly activate reconstituted KCa channels. Am. J. Physiol. 275, L423-L431.
Takahashi, K., Capdevila, J., Karara, A., Falck, J. R., Jacobson, H. R., and Badr, K. F. (1990) Cytochrome P-450 arachidonate metabolites in rat kidney, characterization, and hemodynamic responses. Am. J. Physiol. 258, F781-F789.
Carroll, M. A., Balazy, M., Margiotta, P., Falck, J. R., and McGiff, J. C. (1993) Renal vasodilator activity of 5, 6-epoxyeicosatrienoic acid depends upon conversion by cyclooxygenase, and release of prostaglandins. J. Biol. Chem. 268, 12,260–12,266.
Carroll, M. A., Schwartzman, M., Capdevila, J., Falck, J. R., and McGiff, J. C. (1987) Vasoactivity of arachidonic acid epoxides. Eur. J. Pharmacol. 138, 281–283.
Carroll, M. A., Garcia, M. P., Falck, J. R., and McGiff, J. C. (1992) Cyclooxygenase dependency of the renovascular actions of cytochrome P450-derived arachidonate metabolites. J. Pharmacol. Exp. Ther. 260, 104–109.
Imig, J. D., Navar, L. G., Roman, R. J., Reddy, K. K., and Falck, J. R. (1996) Actions of epoxygenase metabolites on the preglomerular vasculature. J. Am. Soc. Nephrol. 7, 2364–2370.
Fulton, D., McGiff, J. C., and Quilley, J. (1992) Contribution of NO, and cytochrome P450 to the vasodilator effect of bradykinin in the rat. Br. J. Pharmacol. 107, 722–725.
Zou, A. P., Fleming, J. T., Falck, J. R., Jacobs, E. R., Gebremedhin, D., Harder, D. R., and Roman, R. J. (1996) Stereospecific effects of epoxyeicosatrienoic acids on renal vascular tone, and K+-channel activity. Am. J. Physiol. 270, F822-F832.
Imig, J. D., Inscho, E. W., Deichmann, P. C., Reddy, K. M., and Falck, J. R. (1999) Afferent arteriolar vasodilation to the sulfonimide analog of 11,12-epoxyeicosatrienoic acid involves protein kinase A. Hypertension 33, 408–413.
Vazquez, B., Rios, A., and Escalante, B. (1995) Arachidonic acid metabolism modulates vasopressin-induced renal vasoconstriction. Life Sciences 56, 1455–1466.
Force, T., Hyman, G., Hajjar, R., Sellmayer, A., and Bonventre, J. V. (1991) Non-cyclooxygenase metabolites of arachidonic acid amplify the vasopressin-induced Ca2+ signal in glomerular mesangial cells by releasing Ca2+ from intracellular stores. J. Biol. Chem. 266, 4295–4302.
Arima, S., Endo, Y., Yaoita, H., Omata, K., Ogawa, S., Tsunoda, K., Abe, M., Takeuchi, K., Abe, K., and Ito, S. (1997) Possible Role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in the isolated microperfused rabbit afferent arteriole. J. Clin. Invest. 100, 2816–2823.
Imig, J. D., Pham, B. T., LeBlanc, E. A., Reddy, K. M., Falck, J. R., and Inscho, E. W. (2000) Cytochrome P450, and cyclooxygenase metabolites contribute to the endothelin-1 afferent arteriolar vasoconstrictor and calcium responses. Hypertension 35, 307–312.
Imig, J. D. and Deichmann, P. C. (1997) Afferent arteriolar responses to ANG II involve activation of PLA2, and modulation by lipoxygenase, and P-450 pathways. Am. J. Physiol. 273, F274-F282.
Imig, J. D., Falck, J. R., and Inscho, E. W. (1999) Contribution of cytochrome P450 epoxygenase, and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness. Br. J. Pharmacol. 127, 1399–1405.
Gebremedhin, D., Harder, D. R., Pratt, P. F., and Campbell, W. B. (1998) Bioassay of an endothelium-derived hyperpolarizing factor from bovine coronary arteries, role of a cytochrome P450 metabolite. J. Vas. Res. 35, 274–284.
Oltman, C. L., Weintraub, N. L., VanRollins, M., and Dellsperger, K. C. (1998) Epoxyeicosatrienoic acids, and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation. Cir. Res. 83, 932–939.
Fulton, D., Mahboubi, K., McGiff, J. C., and Quilley, J. (1995) Cytochrome P450-dependent effects of bradykinin in the rat heart. Br. J. Pharmacol. 114, 99–102.
Fulton, D., McGiff, J. C., and Quilley, J. (1999) Pharmacological evaluation of an epoxide as the putative hyperpolarizing factor mediating the nitric oxide-independent vasodilator effect of bradykinin in the rat heart. J. Pharmacol. Exp. Ther. 287, 497–503.
Nishikawa, Y., Stepp, D. W., and Chilian, W. M. (1999) In vivo location, and mechanism of EDHF -mediated vasodilation in canine coronary microcirculation. Am. J. Physiol. 277, H1252-H1259.
Widmann, M. D., Weintraub, N. L., Fudge, J. L., Brooks, L. A., and Dellsperger, K. C. (1998) Cytochrome P-450 pathway in acetylcholine-induced canine coronary microvascular vasodilation in vivo. Am. J. Physiol. 274, H283-H289.
Weintraub, N. L., Fang, X., Kaduce, T. L., Van Rollins, M., Chatterjee, P., and Spector, A. A. (1997) Potentiation of endothelium-dependent relaxation by epoxyeicosatrienoic acids. Circ. Res. 81, 258–267.
Li, P. L. and Campbell, W. B. (1997) Epoxyeicosatrienoic acids activate K+ channels in coronary smooth muscle through a guanine nucleotide binding protein. Circ. Res. 80, 877–884.
Li, P. L., Zou, A. P., and Campbell, W. B. (1997) Regulation of potassium channels in coronary arterial smooth muscle by endothelium-derived vasodilators. Hypertension 29, 262–267.
Li, P. L., Chen, C. L., Bortell, R., and Campbell, W. B. (1999) 11, 12-Epoxyeicosatrienoic acid stimulates endogenous mono-ADP-ribosylation in bovine coronary arterial smooth muscle. Circ. Res. 85, 349–356.
Zhang, Y., Cribbs, L. L., and Satin, J. (2000) Arachidonic acid modulation of a1H, a cloned human T-type calcium channel. Am. J. Physiol. 278, H184-H193.
Chen, J., Capdevila, J. H., Zeldin, D. C., and Rosenberg, R. L. (1999) Inhibition of cardiac L-type calcium channels by epoxyeicosatrienoic acids. Mol. Pharmacol. 55, 288–295.
Fisslthaler, B., Popp, R., Kiss, L., Potente, M., Harder, D. R., Fleming, I., and Busse, R. (1999) Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401, 493–497.
Alkayed, N. J., Birks, E. K., Hudetz, A. G., Roman, R. J., Henderson, L., and Harder, D. R. (1996) Inhibition of brain P-450 arachidonic acid epoxygenase decreases baseline cerebral blood flow. Am. J. Physiol. 271, H1541-H1546.
Pelligrino, D. A., Santizo, R. A., and Wang, Q. (1999) Miconazole represses CO2 — induced pial arteriolar dilation only under selected circumstances. Am. J. Physiol. 277, H1484-H1490.
Roman, R. J. and Harder, D. R. (1993) Cytochrome P450 metabolites of arachidonic acid in the control of vascular tone, in Mechanoreception by the Vascular Wall (Rubanyi, G. M., ed.), Futura Publishing, Mount Kisco, NY, pp. 155–172.
Ellis, E. F., Police, R. J., Yancey, L., McKinney, J. S., and Amruthesh, S. C. (1990) Dilation of cerebral arterioles by cytochrome P-450 metabolites of arachidonic acid. Am. J. Physiol. 259, H1171-H1177.
Rzigalinski, B. A., Willoughby, K. A., Hoffman, S. W., Falck J. R., and Ellis, E. F. (1999) Calcium influx factor, further evidence it is 5, 6-epoxyeicosatrienoic acid. J. Biol. Chem. 274, 175–182.
Leffler, C. W. and Fedinec, A. L. (1997) Newborn piglet cerebral microvascular responses to epoxyeicosatrienoic acids. Am. J. Physiol. 273, H333-H338.
Munzenmaier, D. H. and Harder, D. R. (2000) Cerebral microvascular endothelial cell tube formation, role of astrocytic epoxyeicosatrienoic acid release. Am. J. Physiol. 278, H1163-H1167.
Stephenson, A. H., Sprague, R. S., and Lonigro, A. J. (1998) 5, 6-Epoxyeicosatrienoic acid reduces increases in pulmonary vascular resistance in the dog. Am. J. Physiol. 275, H100-H109.
Tan, J. Z., Kaley, G., and Gurtner, G. H. (1997) Nitric oxide, and prostaglandins mediate vasodilation to 5, 6-EET in rabbit lung. Adv. Exp. Biol. Med. 407, 561–566.
Ivey, C. L., Stephenson, A. H., and Townsley, M. I. (1998) Involvement of cytochrome P450 enzyme activity in the control of microvascular permeability in canine lung. Am. J. Physiol. 275, L756-L763.
Baron, A., Frieden, M., and Beny, J. L. (1997) Epoxyeicosatrienoic acids activate a high-conductance, Ca2+-dependent K+ channel on pig coronary artery endothelial cells. J. Physiol. 504, 537–543.
Chataigneau, T., Feletou, M., Duhault, J., and Vanhoutte, P. M. (1998) Epoxyeicosatrienoic acids, potassium channel blockers, and endothelium-dependent hyperpolarization in the guinea-pig. Br. J. Pharmacol. 123, 574–580.
Hoebel, B. G., Steyrer, E., and Graier, W. F. (1999) Origin, and function of epoxyeicosatrienoic acids in vascular endothelial cells, more than just endothelium-derived hyperpolarizing factor? Clin. Exp. Pharmacol. Physiol. 25, 826–830.
Proctor, K. G., Falck, J. R., and Capdevila, J. (1987) Intestinal vasodilation by epoxyeicosatrienoic acids, arachidonic acid metabolites produced by a cytochrome P450 monooxygenase. Circ. Res. 60, 50–59.
Chen, G. and Cheung, D. W. (1996) Modulation of endothelium-dependent hyperpolarization, and relaxation to acetylcholine in rat mesenteric artery by cytochrome P450 enzyme activity. Circ. Res. 79, 827–833.
Fujimoto, S., Ikegami, Y., Isaka, M., Kato, T., Nihimura, K., and Itoh, T. (1999) K+ channel blockers, and cytochrome P450 inhibitors on acetylcholine-induced, endothelium-dependent relaxation in rabbit mesenteric artery. Eur. J. Pharmacol. 384, 7–15.
Fukao, M., Hattori, Y., Kanno, M., Sakuma, I., and Kitabatake, A. (1997) Evidence against a role of cytochrome P450-derived arachidonic acid metabolites in endothelium-dependent hyperpolarization by acetylcholine in rat isolated mesenteric artery. Br. J. Pharmacol. 120, 439–446.
Edwards, G., Gardener, M. J., Feletou, M., Brady, G., Vanhoutte, P. M., and Weston, A. H. (1996) Further investigation of endothelium-derived hyperpolarizing factor (EDHF) in rat hepatic artery, studies using 1-EBIO and ouabain. Br. J. Pharmacol. 128, 1064–1070.
Zygmunt, P. M., Edwards, G., Weston, A. H., Davis, S. C., and Hogestatt, E. D. (1996) Effects of cytochrome P450 inhibitors on EDHF-mediated relaxation in rat hepatic artery. Br. J. Pharmacol. 118, 1147–1152.
Dong, H., Waldron, G. J., Galipeau, D., Cole, W. C., and Triggle, C. R. (1997) NO/PGI2-independent vasorelaxation, and the cytochrome P450 pathway in rabbit carotid artery. Br. J. Pharmacol. 120, 695–701.
Bolz, S. S., Fisslthaler, B., Pieperhoff, S., Wit, C. D., Fleming, I., Busse, R., and Pohl, U. (2000) Antisense oligonucleotides against cytochrome P450 2C8 attenuate EDHF-mediated Ca2+ changes, and dilation in isolated resistance arteries. FASEB J. 14, 255–260.
Shivachar, A. C., Willoughby, K. A., and Ellis, E. F. (1995) Effect of protein kinase C modulators on 14, 15-epoxyeicosatrienoic acid incorporation into astroglial phospholipids. J. Neurochem. 65, 338–346.
Wong, P. Y., Lin, K. T., Yan, Y. T., Ahern, D., Iles, J., Shen, S. Y., Bhatt, R. K., and Falck, J. R. (1993) 14(R), 15(S)-Epoxyeicosatrienoic acid (14(R), 15(S)-EET) receptor in guinea pig mononuclear cell membranes. J. Lip. Med. 6, 199–208.
Barclay, T. B., Peters, J. M., Sewer, M. B., Ferrari, L., Gonzalez, F. J., and Morgan, E. T. (1999) Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific, and peroxisome proleiferator-activated receptor α dependent. J. Pharmacol. Exp. Ther. 290, 1250–1257.
Diczfalusy, U. (1994) β-Oxidation of eicosanoids. Prog. Lipid Res. 33, 403–428.
Yu, Z., Huse, L. M., Adler, P., Graham, L., Ma, J., Zeldin, D. C., and Kroetz, D. L. (2000) Increased CYP2J expression, and epoxyeicosatrienoic acid formation in spontaneously hypertensive rat kidney. Mol. Pharmacol. 57, 1011–1020.
Oleksiak, M. F., Wu, S., Parker, C., Karchner, S. I., Stegeman, J. J., and Zeldin, D. C. (2000) Identification, functional characterization, and regulation of a new cytochrome P450 subfamily, the CYP2Ns. J. Biol. Chem. 275, 2312–2321.
Pfister, S. L., Spitzbarth, N., Nithipatikom, K., Edgemond, W. S., Falck, J. R., and Campbell, W. B. (1998) Identification of the 11, 14, 15-, and 11, 12, 15-trihydroxyeicosatrienoic acids as endothelium-derived relaxing factors of rabbit aorta. J. Biol. Chem. 273, 30,879–30,887.
Fang, X., Kaduce, T. L., Weintraub, N. L., VanRollins, M., and Spector, A. A. 91996) Functional implications of a newly characterized pathway of 11, 12-epoxyeicosatrienoic acid metabolism in arterial smooth muscle. Circ. Res. 79, 784–793.
Nithipatikom, K., Falck, J. R., Bhatt, R. K., Hanke, C. J., and Campbell, W. B. (1997) Determination of 14, 15-epoxyeicosatrienoic acid, and 14, 15-dihydroxyeicosatrienoic acid by fluorimmunoassay. Analyt. Biochem. 246, 253–259.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Imig, J.D. Epoxygenase metabolites. Mol Biotechnol 16, 233–251 (2000). https://doi.org/10.1385/MB:16:3:233
Issue Date:
DOI: https://doi.org/10.1385/MB:16:3:233