Vitamin C activation of the biosynthesis of epoxyeicosatrienoic acids

Abstract

The cardiovascular effects of vitamin C (VitC) could be mediated by epoxyeicosatrienoic acids (EETs). We aimed to study the mechanism of VitC-dependent microsomal formation of cis- and trans-EETs and the regulation of EET levels in rat isolated perfused kidneys and in vivo. VitC biphasically stimulated rat kidney microsomal cis- and trans-EET formation in a ratio of 1:2, involving the participation of lipid hydroperoxides (LOOHs), Fe2+ , and cytochrome P450 (CYP). Levels of LOOHs correlated with microsomal EET production. LOOH stimulation of CYP isoforms resulted in preferred trans- over cis-EET formation from arachidonic acid and was associated with the cleavage of LOOHs, which indicated a CYP peroxy-genase activity. EETs contributed to VitC-induced vasodilator responses in rat isolated perfused kidneys. VitC (1 mg/ml) given in the drinking water for 9 days doubled rat urinary EET excretion, increased plasma levels of EETs, mostly trans-EETs, by 40%, and reduced plasma levels of 20-hydroxyeicosatetraenoic acid. Depletion of VitC in brain cortex and kidney tissues by more than 20- and 50-fold, respectively, in gulonolactone oxidase-knockout mice was associated with mild increases in tissue EETs. These data suggest that LOOHs are a determinant factor for EET formation in vivo in which VitC exerts a key regulatory effect. VitC-activated CYP peroxygenase activity may represent a CYP interaction with lipoxygenases and cyclooxygenases to mediate the cardiovascular effects of VitC via formation of EETs.

Share and Cite:

Jiang, H. , Harrison, F. , Jain, K. , Benjamin, S. , May, J. , Graves, J. , Zeldin, D. , Falck, J. , Hammock, B. and McGiff, J. (2012) Vitamin C activation of the biosynthesis of epoxyeicosatrienoic acids. Advances in Bioscience and Biotechnology, 3, 204-218. doi: 10.4236/abb.2012.33029.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Frei, B., England, L. and Ames, B.N. (1989) Ascorbate is an outstanding antioxidant in human blood plasma. Proceedings of the National Academy of Sciences USA, 86, 6377-6381.
[2] Block, G., Jensen, C.D., Norkus, E.P., Hudes, M. and Crawford, P.B. (2008) Vitamin C in plasma is inversely related to blood pressure and change in blood pressure during the previous year in young Black and White women. Nutrition Journal, 7, 35. doi:10.1186/1475-2891-7-35
[3] Drossos, G.E., Toumpoulis, I.K., Katritsis, D.G., Ioannidis, J.P., Kontogiorgi, P., Svarna, E. and Anagnostopoulos, C.E. (2003) Is vitamin C superior to diltiazem for radial artery vasodilation in patients awaiting coronary artery bypass grafting? Journal of Thoracic and Cardio-vascular Surgery, 125, 330-335. doi:10.1067/mtc.2003.3
[4] Duffy, S.J., Gokce, N., Holbrook, M., Hunter, L.M., Biegelsen, E.S., Huang, A., Keaney, J.F. Jr. and Vita, J.A. (2001) Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension. American Journal of Physiology—Heart and Circulatory Physiology, 280, H528-H534.
[5] Rossig, L., Hoffmann, J., Hugel, B., Mallat, Z., Haase, A., Freyssinet, J.M., Tedgui, A., Aicher, A., Zeiher, A.M. and Dimmeler, S. (2001) Vitamin C inhibits endothelial cell apoptosis in congestive heart failure. Circulation, 104, 2182-2187. doi:10.1161/hc4301.098284
[6] Giusti-Paiva, A. and Domingues, V.G. (2010) Centrally administered ascorbic acid induces antidiuresis, natriure- sis and neurohypo-physeal hormone release in rats. Neuro-Endocrinology Letters, 31, 87-91.
[7] Jackson, T.S., Xu, A., Vita, J.A. and Keaney, J.F. Jr. (1998) Ascorbate prevents the interaction of superoxide and nitric oxide only at very high physiological concentrations. Circulation Research, 83, 916-922.
[8] Pfister, S.L., Gauthier, K.M. and Campbell, W.B. (2010) Vascular pharmacology of epoxyeico-satrienoic acids. Advances in Pharmacology, 60, 27-59. doi:10.1016/B978-0-12-385061-4.00002-7
[9] Elmarakby, A.A. (2012) Reno-protective mechanisms of epox-yeicosatrienoic acids in cardiovascular disease. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 302, R321-R330.
[10] Jiang, H., Quilley, J., Doumad, A.B., Zhu, A.G., Falck, J. R., Hammock, B.D., Stier, C.T. Jr. and Carroll, M.A. (2011) Increases in plasma trans-EETs and blood pressure reduction in spontaneously hypertensive rats. American Journal of Physiology—Heart and Circulatory Physiology, 300, H1990-H1996.
[11] Node, K., Huo, Y., Ruan, X., Yang, B., Spiecker, M., Ley, K., Zeldin, D.C. and Liao, J.K. (1999) Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science, 285, 1276-1279. doi:10.1126/science.285.5431.1276
[12] Nithipatikom, K. and Gross, G.J. (2010) Review article: Epoxyeicosa-trienoic acids: Novel mediators of cardio- protection. Journal of Cardiovascular and Pharmacology and The-rapeutics, 15, 112-119. doi:10.1177/1074248409358408
[13] Taddei, S., Virdis, A., Ghiadoni, L., Magagna, A. and Salvetti, A. (1998) Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation, 97, 2222-2229.
[14] Edwards, D.H., Chaytor, A.T., Bakker, L.M. and Griffith, T.M. (2007) Modulation of gapjunction-dependent arterial relaxation by ascorbic acid. Journal of Vascular Research, 44, 410-422. doi:10.1159/000104254
[15] Campbell, W.B. and Flem-ing, I. (2010) Epoxyeicosatrienoic acids and endothe-lium-dependent responses. Pflugers Arch—European Journal of Physiology, 459, 881-895.
[16] Popp, R., Brandes, R.P., Ott, G., Busse, R. and Fleming, I. (2002) Dynamic modulation of interendothelial gap junctional communication by 11,12-epoxyeicosatrienoic acid. Circulation Research, 90, 800-806. doi:10.1161/01.RES.0000015328.20581.D6
[17] Papoulidis, P., Ananiadou, O., Chalvatzoulis, E., Ampat- zidou, F., Koutsogiannidis, C., Karaiskos, T., Madesis, A. and Drossos, G. (2011) The role of ascorbic acid in the prevention of atrial fibrillation after elective on-pump myo-cardial revascularization surgery: A single-center experience—A pilot study. Interactive Cardiovasc Thoracic Surgery, 12, 121-124.
[18] Padayatty, S.J., Katz, A., Wang, Y., Eck, P., Kwon, O., Lee, J.H., Chen, S., Corpe, C., Dutta, A., Dutta, S.K. and Levine, M. (2003) Vitamin C as an antioxidant: Evaluation of its role in disease prevention. Journal of the American College of Nutrition, 22, 18-35.
[19] Jiang, H., McGiff, J.C., Quilley, J., Sacerdoti, D., Reddy, L.M., Falck, J.R., Zhang, F., Lerea, K.M. and Wong, P.Y. (2004) Identification of 5,6-trans-epoxyeicosatrienoic acid in the phospholipids of red blood cells. The Journal of Biological Chemistry, 279, 36412-36418. doi:10.1074/jbc.M403962200
[20] Bui, P.H., Hsu, E.L. and Hankinson, O. (2009) Fatty acid hydroperoxides support cytochrome P450 2S1-mediated bioactivation of benzo[a]pyrene-7,8-dihydrodiol. Molecular Pharmacol-ogy, 76, 1044-1052. doi:10.1124/mol.109.057760
[21] McCallum, G.P., Weedon, A.C., Krug, P. and Bend, J.R. (1996) Micro-somal cytochrome P450 peroxygenase metabolism of arachidonic acid in guinea pig liver. Journal of Pharmacology and Experimental Therapeutics, 278, 1188-1194.
[22] Brash, A.R., Chang, M.S., Funk, C.D. and Song, W. (1994) Novel transformations of HPETEs by cytochrome P450s. Annals of the New York Academy of Sciences, 744, 25-30. doi:10.1111/j.1749-6632.1994.tb52720.x
[23] Joo, H., Lin, Z. and Arnold, F.H. (1999) Laboratory evo- lution of peroxide-mediated cytochrome P450 hydroxyla- tion. Nature, 399, 670-673. doi:10.1038/21395
[24] Capdevila, J., Saeki, Y. and Falck, J.R. (1984) The mecha- nistic plu-rality of cytochrome P-450 and its biological ramifications. Xenobiotica, 14, 105-118. doi:10.3109/00498258409151401
[25] Jiang, H., Zhu, A.G., Mamczur, M., Morisseau, C., Ham- mock, B.D., Falck, J.R. and McGiff, J.C. (2008) Hydrolysis of cis- and trans-epoxyeicosatrienoic acids by rat red blood cells. Journal of Pharmacology and Experimental Therapeutics, 326, 330-337. doi:10.1124/jpet.107.134858
[26] Sato, P.H. and Zannoni, V.G. (1976) Ascorbic acid and hepatic drug metabolism. Journal of Pharmacology and Experimental Therapeutics, 198, 295-307.
[27] 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. Archives of Biochemistry and Biophysocs, 322, 76-86.
[28] Chen, Y.J., Jiang, H. and Quilley, J. (2003) The nitric oxide- and prostaglandin-independent component of the renal vasodilator effect of thimerosal is mediated by epoxyeicosatrienoic acids. Journal of Pharmacology and Experimental Therapeutics, 304, 1292-1298. doi:10.1124/jpet.102.042671
[29] Harrison, F.E., Yu, S.S., Van Den Bossche, K.L., Li, L., May, J.M. and McDonald, M.P. (2008) Elevated oxida- tive stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid. Journal of Neurochemistry, 106, 1198-1208. doi:10.1111/j.1471-4159.2008.05469.x
[30] Deved, V., Poyah, P., James, M.T., Tonelli, M., Manns, B. J., Walsh, M. and Hemmelgarn, B.R. (2009) Ascorbic acid for ane-mia management in hemodialysis patients: A systematic review and meta-analysis. American Journal of Kidney Disease, 54, 1089-1097. doi:10.1053/j.ajkd.2009.06.040
[31] Bridges, K.R. and Hoffman, K.E. (1986) The effects of ascorbic acid on the intracellular metabolism of iron and ferritin. Journal of Biological Chemistry, 261, 14273-14277.
[32] Nelli, S., Craig, J. and Martin, W. (2009) Oxidation by trace Cu2+ ions underlies the ability of ascorbate to induce vascular dysfunction in the rat perfused mesentery. European Journal of Pharmacology, 614, 84-90. doi:10.1016/j.ejphar.2009.04.033
[33] Schwartzman, M.L., Davis, K.L., McGiff, J.C., Levere, R.D. and Abra-ham, N.G. (1988) Purification and characterization of cytochrome P-450-dependent arachidonic acid epoxyge-nase from human liver. Journal of Biological Chemistry, 263, 2536-2542.
[34] Rifkind, A.B., Lee, C., Chang, T.K. and Waxman, D.J. (1995) Arachidonic acid metabolism by human cyto- chrome P450s 2C8, 2C9, 2E1, and 1A2: Regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver micro- somes. Archives of Biochemistry and Biophysics, 320, 380-389. doi:10.1016/0003-9861(95)90023-3
[35] Muindi, J.F. and Young, C.W. (1993) Lipid hydroperoxides greatly increase the rate of oxidative catabolism of all-transretinoic acid by human cell culture microsomes genetically enriched in specified cytochrome P-450 iso- forms. Cancer Research, 53, 1226-1229.
[36] Norio, K., Wikstrom, M., Salmela, K., Kyllonen, L. and Lindgren, L. (2003) Ascorbic acid against reperfusion injury in human renal transplantation. Transplant International, 16, 480-485. doi:10.1111/j.1432-2277.2003.tb00352.x
[37] Williams, M.J., Sutherland, W.H., McCormick, M.P., de Jong, S.A., McDonald, J.R. and Walker, R.J. (2001) Vitamin C improves endothelial dysfunction in renal allo- graft recipients. Nephrology Dialysis Transplantation, 16, 1251-1255. doi:10.1093/ndt/16.6.1251
[38] Yue, H., Jansen, S.A., Strauss, K.I., Borenstein, M.R., Barbe, M.F., Rossi, L.J. and Murphy, E. (2007) A liquid chromato-graphy/mass spectrometric method for simultaneous analysis of arachidonic acid and its endogenous eicosanoid metabolites prostaglandins, dihydroxyeicosa- trienoic acids, hydroxyeicosatetraenoic acids, and ep- oxyeicosatrienoic acids in rat brain tissue. Journal of Pharmaceutical and Biomedical Analysis, 43, 1122-1134. doi:10.1016/j.jpba.2006.10.009
[39] Labeque, R. and Marnett, L.J. (1987) 10-Hydroperoxy-8, 12-octadecadienoic acid. A diagnostic probe of alkoxyl radical generation in metal-hydroperoxide reactions. Journal of the American Chemical Society, 109, 2828-2829. doi:10.1021/ja00243a048
[40] Schafer, F.Q., Qian, S.Y. and Buettner, G.R. (2000) Iron and free radical oxidations in cell membranes. Cell and Molecular Biology (Noisy-legrand), 46, 657-662.
[41] Vaz, A.D., McGinnity, D.F. and Coon, M.J. (1998) Epoxidation of olefins by cytochrome P450: Evidence from site-specific mutagenesis for hydroperoxo-iron as an electrophilic oxidant. Proceedings of the National Academy of Sciences USA, 95, 3555-3560.
[42] Newcomb, M., Hollenberg, P.F. and Coon, M.J. (2003) Multiple mechanisms and multiple oxidants in P450-catalyzed hydroxylations. Archives of Biochemistry and Biophysics, 409, 72-79. doi:10.1016/S0003-9861(02)00445-9
[43] Maeda, N., Hagihara, H., Nakata, Y., Hiller, S., Wilder, J. and Red-dick, R. (2000) Aortic wall damage in mice unable to synthesize ascorbic acid. Proceedings of the National Academy of Sciences USA, 97, 841-846.
[44] do Carmo, J.M., da Silva, A.A., Morgan, J., Wang, Y.X., Munusamy, S. and Hall, J.E. (2010) Inhibition of soluble epoxide hydrolase reduces food intake and increases metabolic rate in obese mice. Nutrition, Metabolism & Cardiovascular Diseases, in press. doi:10.1016/j.numecd.2010.10.017
[45] Yoshioka, M., Aoyama, K. and Matsushita, T. (1985) Effects of ascorbic acid on blood pressure and ascorbic acid metabolism in spontaneously hypertensive rats (SH rats). International Journal of Vitamin and Nutrition Research, 55, 301-307.

Copyright © 2024 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.