HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lasker, J. M. Articles by Powell, P. K. Search for Related Content PubMed PubMed Citation Articles by Lasker, J. M. Articles by Powell, P. K. Social Bookmarking                      What's this?

J Biol Chem, Vol. 275, Issue 6, 4118-4126, February 11, 2000

Formation of 20-Hydroxyeicosatetraenoic Acid, a Vasoactive and Natriuretic Eicosanoid, in Human Kidney
ROLE OF CYP4F2 AND CYP4A11^*

Jerome M. Lasker, W. Bill Chen, Imre Wolf, Barbara P. Bloswick^§, Patricia D. Wilson^§, and Pnina K. Powell

From the Departments of Biochemistry and ^§ Medicine, Mount Sinai School of Medicine, New York, New York 10029

20-Hydroxyeicosatetraenoic acid (20-HETE), an -hydroxylated arachidonic acid (AA) metabolite, elicits specific effects on kidney vascular and tubular function that, in turn, influence blood pressure control. The human kidney's capacity to convert AA to 20-HETE is unclear, however, as is the underlying P450 catalyst. Microsomes from human kidney cortex were found to convert AA to a single major product, namely 20-HETE, but failed to catalyze AA epoxygenation and midchain hydroxylation. Despite the monophasic nature of renal AA -hydroxylation kinetics, immunochemical studies revealed participation of two P450s, CYP4F2 and CYP4A11, since antibodies to these enzymes inhibited 20-HETE formation by 65.9 ± 17 and 32.5 ± 14%, respectively. Western blotting confirmed abundant expression of these CYP4 proteins in human kidney and revealed that other AA-oxidizing P450s, including CYP2C8, CYP2C9, and CYP2E1, were not expressed. Immunocytochemistry showed CYP4F2 and CYP4A11 expression in only the S2 and S3 segments of proximal tubules in cortex and outer medulla. Our results demonstrate that CYP4F2 and CYP4A11 underlie conversion of AA to 20-HETE, a natriuretic and vasoactive eicosanoid, in human kidney. Considering their proximal tubular localization, these P450 enzymes may partake in pivotal renal functions, including the regulation of salt and water balance, and arterial blood pressure itself.

Portions of this work were presented at the 1998 Annual Meeting of the American Society for Biochemistry and Molecular Biology held in May, 1998 in Washington, D. C.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				U. Savas, D. E. W. Machemer, M.-H. Hsu, P. Gaynor, J. M. Lasker, R. H. Tukey, and E. F. Johnson Opposing Roles of Peroxisome Proliferator-activated Receptor {alpha} and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model J. Biol. Chem., June 12, 2009; 284(24): 16541 - 16552. [Abstract] [Full Text] [PDF]

				K. Sugimoto, H. Akasaka, T. Katsuya, K. Node, T. Fujisawa, I. Shimaoka, O. Yasuda, M. Ohishi, T. Ogihara, K. Shimamoto, et al. A Polymorphism Regulates CYP4A11 Transcriptional Activity and Is Associated With Hypertension in a Japanese Population Hypertension, December 1, 2008; 52(6): 1142 - 1148. [Abstract] [Full Text] [PDF]

				M. Fer, L. Corcos, Y. Dreano, E. Plee-Gautier, J.-P. Salaun, F. Berthou, and Y. Amet Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism J. Lipid Res., November 1, 2008; 49(11): 2379 - 2389. [Abstract] [Full Text] [PDF]

				C. Fava, M. Montagnana, P. Almgren, L. Rosberg, G. Lippi, B. Hedblad, G. Engstrom, G. Berglund, P. Minuz, and O. Melander The V433M Variant of the CYP4F2 Is Associated With Ischemic Stroke in Male Swedes Beyond Its Effect on Blood Pressure Hypertension, August 1, 2008; 52(2): 373 - 380. [Abstract] [Full Text] [PDF]

				N. C. Ward, I-J. Tsai, A. Barden, F. M. van Bockxmeer, I. B. Puddey, J. M. Hodgson, and K. D. Croft A Single Nucleotide Polymorphism in the CYP4F2 but not CYP4A11 Gene Is Associated With Increased 20-HETE Excretion and Blood Pressure Hypertension, May 1, 2008; 51(5): 1393 - 1398. [Abstract] [Full Text] [PDF]

				H. Liu, Y. Zhao, D. Nie, J. Shi, L. Fu, Y. Li, D. Yu, and J. Lu Association of a Functional Cytochrome P450 4F2 Haplotype with Urinary 20-HETE and Hypertension J. Am. Soc. Nephrol., April 1, 2008; 19(4): 714 - 721. [Abstract] [Full Text] [PDF]

				M. Dhar, D. W. Sepkovic, V. Hirani, R. P. Magnusson, and J. M. Lasker Omega oxidation of 3-hydroxy fatty acids by the human CYP4F gene subfamily enzyme CYP4F11 J. Lipid Res., March 1, 2008; 49(3): 612 - 624. [Abstract] [Full Text] [PDF]

				D. E. Stec, R. J. Roman, A. Flasch, and M. J. Rieder Functional polymorphism in human CYP4F2 decreases 20-HETE production Physiol Genomics, June 19, 2007; 30(1): 74 - 81. [Abstract] [Full Text] [PDF]

				N. T. Snider, A. M. Kornilov, U. M. Kent, and P. F. Hollenberg Anandamide Metabolism by Human Liver and Kidney Microsomal Cytochrome P450 Enzymes to Form Hydroxyeicosatetraenoic and Epoxyeicosatrienoic Acid Ethanolamides J. Pharmacol. Exp. Ther., May 1, 2007; 321(2): 590 - 597. [Abstract] [Full Text] [PDF]

				M.-H. Hsu, U. Savas, K. J. Griffin, and E. F. Johnson Regulation of Human Cytochrome P450 4F2 Expression by Sterol Regulatory Element-binding Protein and Lovastatin J. Biol. Chem., February 23, 2007; 282(8): 5225 - 5236. [Abstract] [Full Text] [PDF]

				S. P. Levick, D. C. Loch, S. M. Taylor, and J. S. Janicki Arachidonic Acid Metabolism as a Potential Mediator of Cardiac Fibrosis Associated with Inflammation J. Immunol., January 15, 2007; 178(2): 641 - 646. [Abstract] [Full Text] [PDF]

				P. Christmas, K. Tolentino, V. Primo, K. Z. Berry, R. C. Murphy, M. Chen, D. M. Lee, and R. J. Soberman Cytochrome P-450 4F18 Is the Leukotriene B4 {omega}-1/{omega}-2 Hydroxylase in Mouse Polymorphonuclear Leukocytes: IDENTIFICATION AS THE FUNCTIONAL ORTHOLOGUE OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE CYP4F3A IN THE DOWN-REGULATION OF RESPONSES TO LTB4 J. Biol. Chem., March 17, 2006; 281(11): 7189 - 7196. [Abstract] [Full Text] [PDF]

				C. Lefevre, B. Bouadjar, V. Ferrand, G. Tadini, A. Megarbane, M. Lathrop, J.-F. Prud'homme, and J. Fischer Mutations in a new cytochrome P450 gene in lamellar ichthyosis type 3 Hum. Mol. Genet., March 1, 2006; 15(5): 767 - 776. [Abstract] [Full Text] [PDF]

				S. L. Miksys, C. Cheung, F. J. Gonzalez, and R. F. Tyndale HUMAN CYP2D6 AND MOUSE CYP2DS: ORGAN DISTRIBUTION IN A HUMANIZED MOUSE MODEL Drug Metab. Dispos., October 1, 2005; 33(10): 1495 - 1502. [Abstract] [Full Text] [PDF]

				N. Miyata, T. Seki, Y. Tanaka, T. Omura, K. Taniguchi, M. Doi, K. Bandou, S. Kametani, M. Sato, S. Okuyama, et al. Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N'-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 77 - 85. [Abstract] [Full Text] [PDF]

				K. Nithipatikom, E. R. Gross, M. P. Endsley, J. M. Moore, M. A. Isbell, J. R. Falck, W. B. Campbell, and G. J. Gross Inhibition of Cytochrome P450{omega}-Hydroxylase: A Novel Endogenous Cardioprotective Pathway Circ. Res., October 15, 2004; 95(8): e65 - e71. [Abstract] [Full Text] [PDF]

				N. C. Ward, J. Rivera, J. Hodgson, I. B. Puddey, L. J. Beilin, J. R. Falck, and K. D. Croft Urinary 20-Hydroxyeicosatetraenoic Acid Is Associated With Endothelial Dysfunction in Humans Circulation, July 27, 2004; 110(4): 438 - 443. [Abstract] [Full Text] [PDF]

				S. M. Poloyac, M. A. Tortorici, D. I. Przychodzin, R. B. Reynolds, W. Xie, R. F. Frye, and M. A. Zemaitis THE EFFECT OF ISONIAZID ON CYP2E1- AND CYP4A-MEDIATED HYDROXYLATION OF ARACHIDONIC ACID IN THE RAT LIVER AND KIDNEY Drug Metab. Dispos., July 1, 2004; 32(7): 727 - 733. [Abstract] [Full Text] [PDF]

				F. Xu, J. R. Falck, P. R. Ortiz de Montellano, and D. L. Kroetz Catalytic Activity and Isoform-Specific Inhibition of Rat Cytochrome P450 4F Enzymes J. Pharmacol. Exp. Ther., March 1, 2004; 308(3): 887 - 895. [Abstract] [Full Text] [PDF]

				C. L. Laffer, M. Laniado-Schwartzman, A. Nasjletti, and F. Elijovich 20-HETE and Circulating Insulin in Essential Hypertension With Obesity Hypertension, February 1, 2004; 43(2): 388 - 392. [Abstract] [Full Text] [PDF]

				C. L. Laffer, M. Laniado-Schwartzman, M.-H. Wang, A. Nasjletti, and F. Elijovich Differential Regulation of Natriuresis by 20-Hydroxyeicosatetraenoic Acid in Human Salt-Sensitive Versus Salt-Resistant Hypertension Circulation, February 4, 2003; 107(4): 574 - 578. [Abstract] [Full Text] [PDF]

				D. E. Stec, A. Flasch, R. J. Roman, and J. A. White Distribution of cytochrome P-450 4A and 4F isoforms along the nephron in mice Am J Physiol Renal Physiol, January 1, 2003; 284(1): F95 - F102. [Abstract] [Full Text] [PDF]

				F. Xu, W. O. Straub, W. Pak, P. Su, K. G. Maier, M. Yu, R. J. Roman, P. R. Ortiz De Montellano, and D. L. Kroetz Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid omega -hydroxylase activity Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2002; 283(3): R710 - R720. [Abstract] [Full Text] [PDF]

				T. J. Sontag and R. S. Parker Cytochrome P450 omega -Hydroxylase Pathway of Tocopherol Catabolism. NOVEL MECHANISM OF REGULATION OF VITAMIN E STATUS J. Biol. Chem., July 5, 2002; 277(28): 25290 - 25296. [Abstract] [Full Text] [PDF]

				R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]

				V. R. Holla, F. Adas, J. D. Imig, X. Zhao, E. Price Jr., N. Olsen, W. J. Kovacs, M. A. Magnuson, D. S. Keeney, M. D. Breyer, et al. Alterations in the regulation of androgen-sensitive Cyp 4a monooxygenases cause hypertension PNAS, April 24, 2001; 98(9): 5211 - 5216. [Abstract] [Full Text] [PDF]

				B. S. Cummings, J. M. Lasker, and L. H. Lash Expression of Glutathione-Dependent Enzymes and Cytochrome P450s in Freshly Isolated and Primary Cultures of Proximal Tubular Cells from Human Kidney J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 677 - 685. [Abstract] [Full Text]

				P. Christmas, J. P. Jones, C. J. Patten, D. A. Rock, Y. Zheng, S.-M. Cheng, B. M. Weber, N. Carlesso, D. T. Scadden, A. E. Rettie, et al. Alternative Splicing Determines the Function of CYP4F3 by Switching Substrate Specificity J. Biol. Chem., October 5, 2001; 276(41): 38166 - 38172. [Abstract] [Full Text] [PDF]

				F. Kehl, L. Cambj-Sapunar, K. G. Maier, N. Miyata, S. Kametani, H. Okamoto, A. G. Hudetz, M. L. Schulte, D. Zagorac, D. R. Harder, et al. 20-HETE contributes to the acute fall in cerebral blood flow after subarachnoid hemorrhage in the rat Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1556 - H1565. [Abstract] [Full Text] [PDF]