Jorge H. Capdevila

Last updated
Jorge H. Capdevila
Born (1940-10-06) October 6, 1940 (age 84)
Santiago, Chile
Alma mater University of Chile, University of Georgia
OccupationBiochemist
SpouseMaria Antonieta Maturana
Children2

Jorge H. Capdevila (born October 6, 1940) is an American biochemist and professor emeritus of medicine at Vanderbilt University Medical School. [1] He was named fellow of the American Heart Association in 2002 and received the 2004 American Heart Association's "Novartis Excellence Award for Hypertension Research" [2] for his contributions to our understanding of the molecular basis of hypertension. Capdevila's identification of roles for Cytochrome P450 (P450) in the metabolism of arachidonic acid (AA) and of the physiological and pathophysiological importance of these enzymes and their products were recognized in a special section honoring him at the 14th International Winter Eicosanoid Conference (2012). [3] Capdevila received an "Outstanding Achievement Award" from the Eicosanoid Research Foundation at their 15th International Bioactive Lipid Conference (2017). [4] [5]

Contents

Personal life

Capdevila was born in Santiago, Chile. He and his wife, Maria Antonieta Maturana, have two sons.[ citation needed ]

Career

Capdevila obtained a degree in biochemistry in 1969 from the University of Chile, Santiago, Chile, and in 1975 a Ph.D. from the University of Georgia. [1] He did postdoctoral work with Sten Orrenius at the Karolinska Institutet, as well as with Russell A. Prough and Ronald W. Estabrook at the University of Texas Health Science Center at Dallas (now University of Texas Southwestern Medical Center (UTSW)]. [1] He initiated his independent research career in 1984 as a Research Assistant Professor of Biochemistry at the UTSW Medical Center). In 1986 he joined the faculty at the Vanderbilt University Medical School as associate professor of medicine and biochemistry, was promoted to professor in 1991, and retired as emeritus professor of medicine in 2015. [1] Capdevila has authored 206 peer-reviewed publications and was awarded five US patents. [1]

Scientific contributions

The Cytochrome P450 Arachidonic Acid Monooxygenase Metabolic Pathway

After his 1981 report of roles for the microsomal P450 enzymes in AA oxidation, [6] Capdevila initiated studies of the biochemical and enzymatic properties of this novel metabolic pathway [5] that led to the initial: a) structural identification of the 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) [7] and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE) [8] as products of the Epoxygenase Omega Hydroxylase branches of the P450 AA Monooxygenase [5] [9] [10] respectively; and b) characterization of the EETs as products of the in vivo metabolism of AA by rodent and human organs [11] and of the AA epoxygenase as an endogenous metabolic pathway. [9] [10] [11] Subsequently, Capdevila's laboratory identified: a) roles for P450s of the CYP2 gene subfamily in EETs endogenous biosynthesis; [11] b) the presence of novel pools of endogenous glycerolipids containing esterified EET moities; [12] and c) soluble epoxide hydrolase (sEH)(Epoxide hydrolase 2) as the enzyme that catalyzes EET hydration to vic-dihydroxyeicosatrienoic acids (DHETs) prior to their urinary excretion. [9] [13] The development of inhibitors of sEH activity to control organ EET levels and functional properties is an area of current interest. [14]

Characterization of Functional Roles for the Arachidonic Acid Epoxygenase Metabolites

Early studies by Capdevila and collaborators showed that EETs stimulated the release of brain, pituitary, and pancreatic hormones, [5] [9] [10] mediated signaling by epidermal growth factor, [15] inhibited renal Na+ and K+ transport in isolated collecting ducts, [5] [9] [16] [17] and possessed vasodilator properties. [18] These were the first reports of EET-associated in vitro biological activities, and as such, they served as an incentive to subsequent extended studies of the functional roles and physiological/pathophysiological significance of the AA epoxygenase and its metabolites. [19] [20] [21] [22] [23]

Physiological and Pathophysiological Roles of the Arachidonic Acid Monooxygenase Pathway

Capdevila's research group provided unequivocal genetic and biochemical evidence that, as suggested earlier, [24] members of the P450 murine Cyp4a and Cyp2c gene subfamilies participated in the control of systemic blood pressures [25] by showing that targeted disruption of the: a) Cyp4a14 gene caused a type of hypertension that was male-specific and associated with increases in plasma androgens, the renal expression of the Cyp4a12 AA omega hydroxylase, and the biosynthesis of pro-hypertensive 20-HETE. [19] [26] The potential clinical relevance of these studies was highlighted by reports of associations between a functional variant of the human CYP4A11 20-HETE synthase (the T8590C polymorphism) [27] and hypertension in White Americans, [27] [28] hypertension, the progression of kidney disease in African-Americans, [29] and risk of hypertension in German and Japanese cohorts; [30] b) Cyp4a10 gene downregulated the expression of the kidney Cyp2c44 epoxygenase, leading to reductions in renal EET biosynthesis and the development of dietary salt sensitive hypertension; [31] and c) Cyp2c44 gene caused dietary salt-sensitive hypertension linked to reductions in renal EET biosynthesis and excretion, as well as increases in sodium retention in the distal nephron. [32] Abnormalities in the regulation of urinary EET pools in normotensive, dietary salt-sensitive, individuals have been reported. [33] Collectively, these studies identified: a) 20-HETE as a renal vasoconstrictor and pro-hypertensive lipid; [19] [22] [23] [25] and b) 11,12-EET as an endogenous natriuretic and anti-hypertensive mediator. [5] [17] [25] [32] Additionally, they demonstrated that salt-sensitive hypertension could result from either a down regulation or lack of a functional Cyp2c44 epoxygenase. [5] [25] [31] These achievements, highlighted in independent reviews, [19] [20] [21] [22] [23] contributed as an stimulant to ongoing efforts to further define the physiological and pathophysiological relevance of the AA Monooxygenase enzymes and its metabolites, as well as potentially novel targets for drug development.

More recently, Capdevila participated in: a) the identification of roles for the Cyp2c44 epoxygenases and the EETs in tumor vascularization [34] and progression in rodent models of human non-small-cell-lung cancer (NSCLC); [35] and b) in clinical studies showing improved survival in female cases of NSCLC that were carriers of two known reduction of function variants of the human CYP2C9 epoxygenase gene. [36]

In summary, Capdevila and collaborators contributed to the initial discovery and characterization of roles for the CYP450 monooxygenases in the metabolism and bio-activation of endogenous arachidonic acid, the identification of its role in the in vivo regulation of cell, organ, and body physiology, and to its present status as a physiological/pathophysiological important metabolic pathway. [5]

Related Research Articles

<span class="mw-page-title-main">Eicosanoid</span> Class of compounds

Eicosanoids are signaling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid or other polyunsaturated fatty acids (PUFAs) that are, similar to arachidonic acid, around 20 carbon units in length. Eicosanoids are a sub-category of oxylipins, i.e. oxidized fatty acids of diverse carbon units in length, and are distinguished from other oxylipins by their overwhelming importance as cell signaling molecules. Eicosanoids function in diverse physiological systems and pathological processes such as: mounting or inhibiting inflammation, allergy, fever and other immune responses; regulating the abortion of pregnancy and normal childbirth; contributing to the perception of pain; regulating cell growth; controlling blood pressure; and modulating the regional flow of blood to tissues. In performing these roles, eicosanoids most often act as autocrine signaling agents to impact their cells of origin or as paracrine signaling agents to impact cells in the proximity of their cells of origin. Some eicosanoids, such as prostaglandins, may also have endocrine roles as hormones to influence the function of distant cells.

<span class="mw-page-title-main">CYP1A2</span> Enzyme in the human body

Cytochrome P450 1A2, a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of cytochrome P450 enzymes, termed cytochrome P450 epoxygenases. They are nonclassic eicosanoids.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">CYP2C8</span> Gene-coded protein involved in metabolism of xenobiotics

Cytochrome P4502C8 (CYP2C8) is a member of the cytochrome P450 mixed-function oxidase system involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and linoleic acid to their biologically active epoxides.

<span class="mw-page-title-main">CYP2J2</span> Gene of the species Homo sapiens

Cytochrome P450 2J2 (CYP2J2) is a protein that in humans is encoded by the CYP2J2 gene. CYP2J2 is a member of the cytochrome P450 superfamily of enzymes. The enzymes are oxygenases which catalyze many reactions involved in the metabolism of drugs and other xenobiotics) as well as in the synthesis of cholesterol, steroids and other lipids.

<span class="mw-page-title-main">CYP2C18</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2C18 is a protein that in humans is encoded by the CYP2C18 gene.

<span class="mw-page-title-main">CYP4A11</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4A11 is a protein that in humans is codified by the CYP4A11 gene.

<span class="mw-page-title-main">CYP2S1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2S1 is a protein that in humans is encoded by the CYP2S1 gene. The gene is located in chromosome 19q13.2 within a cluster including other CYP2 family members such as CYP2A6, CYP2A13, CYP2B6, and CYP2F1.

<span class="mw-page-title-main">CYP4F8</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F8 is a protein that in humans is encoded by the CYP4F8 gene.

<span class="mw-page-title-main">CYP4F12</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F12 is a protein that in humans is encoded by the CYP4F12 gene.

<span class="mw-page-title-main">CYP4F3</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 4F3, also leukotriene-B(4) omega-hydroxylase 2, is an enzyme that in humans is encoded by the CYP4F3 gene. CYP4F3 encodes two distinct enzymes, CYP4F3A and CYP4F3B, which originate from the alternative splicing of a single pre-mRNA precursor molecule; selection of either isoform is tissue-specific with CYP3F3A being expressed mostly in leukocytes and CYP4F3B mostly in the liver.

Epoxygenases are a set of membrane-bound, heme-containing cytochrome P450 enzymes that metabolize polyunsaturated fatty acids (PUFAs) to epoxide products that have a range of biological activities.

<span class="mw-page-title-main">CYP4F11</span> Protein-coding gene in the species Homo sapiens

CYP4F11 is a protein that in humans is encoded by the CYP4F11 gene. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This gene is part of a cluster of cytochrome P450 genes on chromosome 19. Another member of this family, CYP4F2, is approximately 16 kb away. Alternatively spliced transcript variants encoding the same protein have been found for this gene.

<span class="mw-page-title-main">CYP4A22</span> Protein-coding gene in the species Homo sapiens

CYP4A22 also known as fatty acid omega-hydroxylase is a protein which in humans is encoded by the CYP4A22 gene.

<span class="mw-page-title-main">20-Hydroxyeicosatetraenoic acid</span> Chemical compound

20-Hydroxyeicosatetraenoic acid, also known as 20-HETE or 20-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid, is an eicosanoid metabolite of arachidonic acid that has a wide range of effects on the vascular system including the regulation of vascular tone, blood flow to specific organs, sodium and fluid transport in the kidney, and vascular pathway remodeling. These vascular and kidney effects of 20-HETE have been shown to be responsible for regulating blood pressure and blood flow to specific organs in rodents; genetic and preclinical studies suggest that 20-HETE may similarly regulate blood pressure and contribute to the development of stroke and heart attacks. Additionally the loss of its production appears to be one cause of the human neurological disease, hereditary spastic paraplegia. Preclinical studies also suggest that the overproduction of 20-HETE may contribute to the progression of certain human cancers, particularly those of the breast.

<span class="mw-page-title-main">Epoxydocosapentaenoic acid</span> Group of chemical compounds

Epoxide docosapentaenoic acids are metabolites of the 22-carbon straight-chain omega-3 fatty acid, docosahexaenoic acid (DHA). Cell types that express certain cytochrome P450 (CYP) epoxygenases metabolize polyunsaturated fatty acids (PUFAs) by converting one of their double bonds to an epoxide. In the best known of these metabolic pathways, cellular CYP epoxygenases metabolize the 20-carbon straight-chain omega-6 fatty acid, arachidonic acid, to epoxyeicosatrienoic acids (EETs); another CYP epoxygenase pathway metabolizes the 20-carbon omega-3 fatty acid, eicosapentaenoic acid (EPA), to epoxyeicosatetraenoic acids (EEQs). CYP epoxygenases similarly convert various other PUFAs to epoxides. These epoxide metabolites have a variety of activities. However, essentially all of them are rapidly converted to their corresponding, but in general far less active, vicinal dihydroxy fatty acids by ubiquitous cellular soluble epoxide hydrolase. Consequently, these epoxides, including EDPs, operate as short-lived signaling agents that regulate the function of their parent or nearby cells. The particular feature of EDPs distinguishing them from EETs is that they derive from omega-3 fatty acids and are suggested to be responsible for some of the beneficial effects attributed to omega-3 fatty acids and omega-3-rich foods such as fish oil.

<span class="mw-page-title-main">Epoxyeicosatetraenoic acid</span> Chemical compound

Epoxyeicosatetraenoic acids are a set of biologically active epoxides that various cell types make by metabolizing the omega 3 fatty acid, eicosapentaenoic acid (EPA), with certain cytochrome P450 epoxygenases. These epoxygenases can metabolize EPA to as many as 10 epoxides that differ in the site and/or stereoisomer of the epoxide formed; however, the formed EEQs, while differing in potency, often have similar bioactivities and are commonly considered together.

Cytochrome P450 omega hydroxylases, also termed cytochrome P450 ω-hydroxylases, CYP450 omega hydroxylases, CYP450 ω-hydroxylases, CYP omega hydroxylase, CYP ω-hydroxylases, fatty acid omega hydroxylases, cytochrome P450 monooxygenases, and fatty acid monooxygenases, are a set of cytochrome P450-containing enzymes that catalyze the addition of a hydroxyl residue to a fatty acid substrate. The CYP omega hydroxylases are often referred to as monoxygenases; however, the monooxygenases are CYP450 enzymes that add a hydroxyl group to a wide range of xenobiotic and naturally occurring endobiotic substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the catabolism of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as autocrine signaling agents or on nearby cells as paracrine signaling agents to regulate various functions such as blood pressure control and inflammation.

John Russell "Camille" Falck is an American chemist, Professor of Biochemistry, and holder of the Robert A. Welch Distinguish Chair in Chemistry at the University of Texas Southwestern Medical Center. In 1996 he was awarded the Wilfred T. Doherty Recognition Award from the Dallas-Fort Worth Section of the American Chemical Society and a Recognition Award at the March 10, 2002, Winter Eicosanoid Conference in appreciation of his significant contributions to the chemistry of natural products, and to the identification and functional characterization of the cytochrome P450 (P450) arachidonic acid (AA) monooxygenase metabolic pathway and its metabolites.

References

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  31. 1 2 Nakagawa, K; Holla, VR; Wei, Y; Wang, WH; Gatica, A; Wei, S; Mei, S; Miller, CM; Cha, DR; Price, E; Zent, R; Pozzi, A; Breyer, MD; Guan, Y; Falck, JR; Waterman, MR; Capdevila, JH (2006). "Salt sensitive hypertension is associated with a dysfunctional Cyp4a10 gene and kidney epithelial sodium channel". Journal of Clinical Investigation. 116 (6): 1696–2302. doi:10.1172/JCI27546. PMC   1459070 . PMID   16691295.
  32. 1 2 Capdevila, JH; Pidkovka, N; Mei, S; Gong, Y; Sun, P; Falck, JR; Imig, JD; Harris, RC; Wang, WH (2014). "The Cyp2c44 epoxygenase regulates renal distal sodium excretion and the blood pressure responses to increased dietary salt intake". Journal of Biological Chemistry. 289 (7): 4377–4386. doi: 10.1074/jbc.M113.508416 . PMC   3924300 . PMID   24368771.
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  35. ↑ Skyrpnky, N.; Che, X.; Hu, W.; Su, Y.; Mont, S.; Yang, S.; Gangadhariah, M.; Wei, S.; Falck, J.R.; Jat, J.L.; Zent, R.; Capdevila, J.H.; Pozzi, A. (2014). "PPARα activation can help prevent and treat non-small cell lung cancer". Cancer Research. 74 (2): 62 1–631. doi:10.1158/0008-5472.CAN-13-1928. PMC   3902646 . PMID   24302581.
  36. ↑ Sausville, L.N.; Gangadhariah, M.; Chiusa, M.; Mei, S.; Wei, S.; Zent, R.; Luther, J.M.; Shuey, M.M.; Capdevila, J.H.; Falck, J.R.; Guengerich, F.P.; Williams, S.M.; Pozzi, A. (2018). "The cytochrome P450 slow metabolizers CPY2C9*2 and CYP2C9*3 directly regulate tumorigenesis via reduced epoxyeicosatrienoic acid production". Cancer Research. 78 (17): 4865–4877. doi:10.1158/0008-5472.CAN-17-3977. PMC   6125168 . PMID   30012669.
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