Jorge H. Capdevila

Capdevila was born in Santiago, Chile. He is married to Maria Antonieta Maturana, with whom he has two sons.{{cn|date=July 2024}}

Capdevila earned a degree in biochemistry from the University of Chile in 1969. He later completed his Ph.D. at the University of Georgia in 1975.

His postdoctoral training included work with Sten Orrenius at the Karolinska Institutet (Sweden) and with Russell A. Prough and Ronald W. Estabrook at the University of Texas Health Science Center at Dallas (now the University of Texas Southwestern Medical Center (UTSW). Capdevila began his independent research career in 1984 as a research assistant professor of biochemistry at UT Southwestern.

In 1986, he joined Vanderbilt University Medical School as an associate professor of medicine and biochemistry. He was promoted to full professor in 1991 and retired as professor emeritus of medicine in 2015. Throughout his career, Capdevila authored 206 peer-reviewed publications and holds five U.S. patents.

Following his 1981 report on the involvement of microsomal cytochrome P450 (P450) enzymes in arachidonic acid (AA) oxidation,{{Cite journal |last1=Capdevila |first1=J. |last2=Chacos |first2=N. |last3=Werringloer |first3=J. |last4=Prough |first4=R.A. |last5=Estabrook |first5=R.W. |date=1981 |title=Liver microsomal cytochrome P-450 and the oxidative metabolism of arachidonic acid |journal=Proceedings of the National Academy of Sciences USA |volume=78 |issue=9 |pages=5362–5366 |bibcode=1981PNAS...78.5362C |doi=10.1073/pnas.78.9.5362 |pmc=348745 |pmid=6795631 |doi-access=free}} Capdevila conducted foundational studies on the biochemical and enzymatic properties of this metabolic pathway. These investigations led to two key advances:

1. Structural identification of the 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs){{Cite journal |last1=Chacos |first1=N. |last2=Falck |first2=J.R. |last3=Wixtrom |first3=C. |last4=Capdevila |first4=J. |date=1982 |title=Novel epoxides formed during the liver cytochrome P-450 oxidation of arachidonic acid |url=https://dx.doi.org/10.1016/0006-291x%2882%2991336-5 |journal=Biochemistry and Biophysical Research Communications |volume=104 |issue=3 |pages=916–922 |doi=10.1016/0006-291x(82)91336-5 |pmid=6803794}} and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE){{Cite journal |last1=Manna |first1=S. |last2=Falck |first2=J.R. |last3=Chacos |first3=N. |last4=Capdevila |first4=J. |date=1983 |title=Synthesis of arachidonic acid metabolites produced by purified kidney cortex microsomal cytochrome P-450 |url=https://www.sciencedirect.com/science/article/pii/S0040403900813192 |journal=Tetrahedron Letters |volume=24 |issue=1 |pages=33–36 |doi=10.1016/S0040-4039(00)81319-2}} as products of the epoxygenase and ω-hydroxylase branches of the P450 AA monooxygenase, respectively.{{Cite journal |last1=Capdevila |first1=J.H. |last2=Falck |first2=J.R. |last3=Harris |first3=R.C. |date=2000 |title=Cytochrome P450 and arachidonic acid bioactivation: Molecular and functional properties of the arachidonate monooxygenase |journal=Journal of Lipid Research |volume=41 |issue=2 |pages=271–292 |doi=10.1016/S0022-2275(20)32049-6 |pmid=10963794 |doi-access=free}}{{Cite journal |last1=Capdevila |first1=J.H. |last2=Falck |first2=J.R. |date=2000 |title=Biochemical and molecular characteristics of the cytochrome P450 arachidonic acid monooxygenase |url=https://pubmed.ncbi.nlm.nih.gov/10963794/ |journal=Prostaglandins and Other Lipid Mediators |volume=62 |issue=3 |pages=271–292 |doi=10.1016/s0090-6980(00)00085-x |pmid=10963794}}
2. Characterization of EETs as endogenous metabolites of AA in rodent and human organs,{{Cite journal |last1=Karara |first1=A. |last2=Dishman |first2=E. |last3=Blair |first3=I. |last4=Falck |first4=J.R. |last5=Capdevila |first5=J.H. |date=1989 |title=Cytochrome P-450 controlled stereoselectivity of the hepatic arachidonic acid epoxygenase |journal=Journal of Biological Chemistry |volume=264 |issue=33 |pages=19822–19827 |doi=10.1016/S0021-9258(19)47185-8 |pmid=2584196 |doi-access=free}} establishing the AA epoxygenase pathway as a physiologically relevant system.

Subsequent work by Capdevila's laboratory identified:

• Roles for CYP2 subfamily enzymes in endogenous EET biosynthesis;
• Novel endogenous glycerolipid pools containing esterified EET moieties;{{Cite journal |last1=Karara |first1=A |last2=Dishman |first2=E |last3=Falck |first3=JR |last4=Capdevila |first4=JH |date=1991 |title=Endogenous epoxyeicosatrienoyl-phospholipids. A novel class of cellular glycerolipids containing epoxidized arachidonate moieties |journal=Journal of Biological Chemistry |volume=266 |issue=12 |pages=7561–7569 |doi=10.1016/S0021-9258(20)89484-8 |pmid=1902222 |doi-access=free}}
• Soluble epoxide hydrolase (sEH; Epoxide hydrolase 2) as the enzyme responsible for catalyzing EET hydration to vicinal dihydroxyeicosatrienoic acids (DHETs), a step preceding their urinary excretion.{{Cite journal |last1=Zeldin |first1=DC |last2=Kobayashi |first2=J |last3=Falck |first3=JR |last4=Winder |first4=BS |last5=Hammock |first5=BD |last6=Snapper |first6=JR |last7=Capdevila |first7=JH |date=1993 |title=Regio and enantiofacial selectivity of epoxyeicosatrienoic acid hydration by cytosolic epoxide hydratase |journal=Journal of Biological Chemistry |volume=268 |issue=9 |pages=6402–6407 |doi=10.1016/S0021-9258(18)53266-X |pmid=8454612 |doi-access=free}}

Current research focuses on developing soluble epoxide hydrolase inhibitors to modulate organ-specific EET levels and their biological effects.{{Cite journal |last1=Morisseau |first1=C. |last2=Hammock |first2=B. D. |date=2013 |title=Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health |journal=Annual Review of Pharmacology and Toxicology |volume=53 |pages=37–58 |doi=10.1146/annurev-pharmtox-011112-140244 |pmc=3578707 |pmid=23020295}}

Early studies by Capdevila and collaborators demonstrated that epoxyeicosatrienoic acids (EETs):

• Stimulated the release of hormones in the brain, pituitary gland, and pancreas;
• Modulated signaling by epidermal growth factor;{{cite journal |last1=Chen |first1=J.K. |last2=Capdevila |first2=J.H. |last3=Harris |first3=R.C. |date=2002 |title=Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate metabolites in epithelial cells |journal=Proceedings of the National Academy of Sciences USA |volume=99 |issue=9 |pages=6029–6034 |doi=10.1073/pnas.092671899 |pmid=11983897 |pmc=122896 |doi-access=free }}
• Inhibited renal Na⁺ and K⁺ transport in isolated collecting ducts;{{cite journal |last1=Capdevila |first1=J.H. |date=2007 |title=Regulation of ion transport and blood pressure by cytochrome P450 monooxygenases |url=https://pubmed.ncbi.nlm.nih.gov/17693763/ |journal=Current Opinion in Nephrology and Hypertension |volume=16 |issue=5 |pages=465–470 |doi=10.1097/MNH.0b013e32827ab48c |pmid=17693763|s2cid=38554014 }}{{cite journal |last1=Capdevila |first1=J.H. |last2=Wang |first2=W.H. |date=2013 |title=Role of P450 epoxygenase in regulating renal membrane transport and hypertension |journal=Current Opinion in Nephrology and Hypertension |volume=22 |issue=2 |pages=163–169 |doi=10.1097/MNH.0b013e32835d911e |pmid=23302865|pmc=3893099 }}
• Exhibited vasodilatory effects in vascular tissues.{{cite journal |last1=Procto |first1=K.G. |last2=Falck |first2=J.R. |last3=Capdevila |first3=J. |date=1987 |title=Intestinal vasodilation by epoxyeicosatrienoic acids: Arachidonic acid metabolites produced by a cytochrome P-450 monoxygenase |url=https://pubmed.ncbi.nlm.nih.gov/3105909/ |journal=Circulation Research |volume=60 |issue=1 |pages=50–59 |doi=10.1161/01.res.60.1.50 |pmid=3105909}}

These findings represented the first identification of EET-associated biological activities in vitro and laid the groundwork for subsequent research into the physiological and pathophysiological roles of the arachidonic acid (AA) epoxygenase pathway and its metabolites.{{cite journal |last1=McGiff |first1=JC |last2=Quilley |first2=J. |title=20-Hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids and blood pressure |journal=Current Opinion in Nephrology and Hypertension |date=2001 |volume=10 |issue=2 |pages=231–237 |doi=10.1097/00041552-200103000-00012 |pmid=11224699 |s2cid=44774278 |url=https://pubmed.ncbi.nlm.nih.gov/11224699/ |access-date=18 January 2024}}{{cite journal |last1=Roman |first1=RJ |title=P450 Metabolites of arachidonic acid in the control of cardiovascular function |journal=Physiological Reviews |date=2002 |volume=82 |issue=1 |pages=131–185 |doi=10.1152/physrev.00021.2001 |pmid=11773611 |url=https://pubmed.ncbi.nlm.nih.gov/11773611/#:~:text=Recent%20studies%20have%20indicated%20that,in%20the%20regulation%20of%20renal%2C |access-date=18 January 2024}}{{cite journal |last1=Spector |first1=AA |last2=Fang |first2=X |last3=Snyder |first3=GD |last4=Weintraub |first4=NL |title=Epoxyeicosatrienoic acids (EETs): metabolism and biochemical function |journal=Progress in Lipid Research |date=2004 |volume=43 |issue=1 |pages=55–90 |doi=10.1016/s0163-7827(03)00049-3 |pmid=14636671 |url=https://pubmed.ncbi.nlm.nih.gov/14636671/ |access-date=24 January 2024}}{{cite journal |last1=Fan |first1=Fan |last2=Muroya |first2=Y |last3=Roman |first3=RJ |title=Cytochrome P450 eicosanoids in hypertension and renal disease |journal=Current Opinion in Nephrology and Hypertension |date=2015 |volume=24 |issue=1 |pages=37–46 |doi=10.1097/MNH.0000000000000088 |pmid=25427230 |pmc=4260681 }}{{cite journal |last1=Imig |first1=JD |title=Epoxyeicosanoids in hypertension |journal=Physiological Research |date=2019 |volume=68 |issue=5 |pages=695–704 |doi=10.33549/physiolres.934291 |pmid=31475560 |pmc=6941753 }}

Capdevila's research group provided unequivocal genetic and biochemical evidence that, as suggested earlier,{{Cite journal |last1=Sacerdoti |first1=D |last2=Escalante |first2=B |last3=Abraham |first3=NG |last4=McGiff |first4=JC |last5=Schwartzman |first5=ML |date=1989 |title=Treatment with tin prevents the development of hypertension in spontaneously hypertensives rats |url=https://pubmed.ncbi.nlm.nih.gov/2492116/ |journal=Science |volume=243 |issue=4889 |pages=388–390 |bibcode=1989Sci...243..388S |doi=10.1126/science.2492116 |pmid=2492116 |access-date=25 January 2024}} members of the P450 murine Cyp4a and Cyp2c gene subfamilies participated in the control of systemic blood pressures{{Cite journal |last1=Capdevila |first1=JH |last2=Wang |first2=W |last3=Falck |first3=JR |date=2015 |title=Arachidonic acid monooxygenase: genetic and biochemical approaches to physiological/pathophysiological relevance |journal=Prostaglandins and Other Other Lipid Mediators |volume=120 |pages=40–49 |doi=10.1016/j.prostaglandins.2015.05.004 |pmc=4575609 |pmid=25986599}} 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.{{Cite journal |last1=Holla |first1=VR |last2=Adas |first2=F |last3=Ichihara |first3=S |last4=Price |first4=E |last5=Olsen |first5=N |last6=Kovacs |first6=WJ |last7=Magnuson |first7=MA |last8=Keeney |first8=DS |last9=Breyer |first9=MD |last10=Falck |first10=JR |last11=Waterman |first11=MR |last12=Capdevila |first12=JH |date=2001 |title=Alterations in the regulation of androgen sensitive Cyp4a monooxygenases cause hypertension |journal=Proceedings of the National Academy of Sciences USA |volume=98 |issue=9 |pages=5211–5216 |bibcode=2001PNAS...98.5211H |doi=10.1073/pnas.081627898 |pmc=33189 |pmid=11320253 |doi-access=free}} 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){{Cite journal |last1=Gainer |first1=JV |last2=Bellamine |first2=A |last3=Dawson |first3=EP |last4=Womble |first4=KE |last5=Grant |first5=SW |last6=Wang |first6=Y |last7=Cupples |first7=A |last8=Guo |first8=CY |last9=Demissie |first9=S |last10=O'Donnell |first10=CJ |last11=Brown |first11=NJ |last12=Waterman |first12=MR |last13=Capdevila |first13=JH |date=2005 |title=A functional variant of CYP4A11 20-HETE synthase is associated with essential |url=https://pubmed.ncbi.nlm.nih.gov/15611369/ |journal=Circulation |volume=111 |issue=1 |pages=63–69 |doi=10.1161/01.CIR.0000151309.82473.59 |pmid=15611369 |s2cid=2157088 |access-date=25 January 2024}} and hypertension in White Americans,{{Cite journal |last1=Williams |first1=JS |last2=Hopkins |first2=PN |last3=Jeunemaitre |first3=C |last4=Brown |first4=NJ |date=2011 |title=CYP4A11 T8590C polymorphism, salt sensitive hypertension, and renal blood flow |journal=Journal of Hypertension |volume=29 |issue=10 |pages=1913–1918 |doi=10.1097/HJH.0b013e32834aa786 |pmc=3309034 |pmid=21873888}} hypertension, the progression of kidney disease in African-Americans,{{Cite journal |last1=Gainer |first1=JV |last2=Lipkowitz |first2=MS |last3=Yu |first3=C |last4=Waterman |first4=MR |last5=Dawson |first5=EP |last6=Capdevila |first6=JH |last7=Brown |first7=NJ |last8=AASK Study Group |date=2008 |title=Association of a CYP4A11 variant and blood pressure in black men |journal=Journal of the American Society of Nephrology |volume=19 |issue=8 |pages=1606–1612 |doi=10.1681/ASN.2008010063 |pmc=2488260 |pmid=18385420}} and risk of hypertension in German and Japanese cohorts;{{Cite journal |last1=Zhang |first1=C |last2=Wang |first2=L |last3=Liao |first3=Q |last4=Zhang |first4=L |last5=Xu |first5=L |last6=Chen |first6=C |last7=Ye |first7=H |last8=Xu |first8=X |last9=Ye |first9=M |last10=Duan |first10=S |date=2013 |title=Genetic associations with hypertension: Meta-Analysis of six candidate genetic variants |journal=Genetic Testing and Molecular Biomarkers |volume=17 |issue=10 |pages=736–742 |doi=10.1089/gtmb.2013.0080 |pmc=3780324 |pmid=23859711}} 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;{{Cite journal |last1=Nakagawa |first1=K |last2=Holla |first2=VR |last3=Wei |first3=Y |last4=Wang |first4=WH |last5=Gatica |first5=A |last6=Wei |first6=S |last7=Mei |first7=S |last8=Miller |first8=CM |last9=Cha |first9=DR |last10=Price |first10=E |last11=Zent |first11=R |last12=Pozzi |first12=A |last13=Breyer |first13=MD |last14=Guan |first14=Y |last15=Falck |first15=JR |date=2006 |title=Salt sensitive hypertension is associated with a dysfunctional Cyp4a10 gene and kidney epithelial sodium channel |journal=Journal of Clinical Investigation |volume=116 |issue=6 |pages=1696–2302 |doi=10.1172/JCI27546 |pmc=1459070 |pmid=16691295 |last16=Waterman |first16=MR |last17=Capdevila |first17=JH}} 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.{{Cite journal |last1=Capdevila |first1=JH |last2=Pidkovka |first2=N |last3=Mei |first3=S |last4=Gong |first4=Y |last5=Sun |first5=P |last6=Falck |first6=JR |last7=Imig |first7=JD |last8=Harris |first8=RC |last9=Wang |first9=WH |date=2014 |title=The Cyp2c44 epoxygenase regulates renal distal sodium excretion and the blood pressure responses to increased dietary salt intake |journal=Journal of Biological Chemistry |volume=289 |issue=7 |pages=4377–4386 |doi=10.1074/jbc.M113.508416 |pmc=3924300 |pmid=24368771 |doi-access=free}} Abnormalities in the regulation of urinary EET pools in normotensive, dietary salt-sensitive, individuals have been reported.{{Cite journal |last1=Elijovich |first1=F |last2=Milne |first2=GL |last3=Brown |first3=NJ |last4=Schwartzman |first4=ML |last5=Laffer |first5=CL |date=2018 |title=Two pools of epoxyeicosatrienoic acids in humans. alterations in salt-sensitive normotensive subjects |journal=Hypertension |volume=71 |issue=2 |pages=346–355 |doi=10.1161/HYPERTENSIONAHA.117.10392 |pmc=5764817 |pmid=29279315}} Collectively, these studies identified: a) 20-HETE as a renal vasoconstrictor and pro-hypertensive lipid; and b) 11,12-EET as an endogenous natriuretic and anti-hypertensive mediator. Additionally, they demonstrated that salt-sensitive hypertension could result from either a down regulation or lack of a functional Cyp2c44 epoxygenase. These achievements, highlighted in independent reviews, 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{{Cite journal |last1=Pozzi |first1=A. |last2=Popescu |first2=V. |last3=Yang |first3=S. |last4=Mei |first4=S. |last5=Shi |first5=M. |last6=Puolitaival |first6=S. |last7=Caprioli |first7=R.M. |last8=Capdevila |first8=J.H. |date=2010 |title=The anti-tumorigenic properties of the peroxisomal proliferator-activated receptor alpha are arachidonic acid epoxygenase-mediated |journal=Journal of Biological Chemistry |volume=285 |issue=17 |pages=12840–12850 |doi=10.1074/jbc.M109.081554 |pmc=2857132 |pmid=20178979 |doi-access=free}} and progression in rodent models of human non-small-cell-lung cancer (NSCLC);{{Cite journal |last1=Skyrpnky |first1=N. |last2=Che |first2=X. |last3=Hu |first3=W. |last4=Su |first4=Y. |last5=Mont |first5=S. |last6=Yang |first6=S. |last7=Gangadhariah |first7=M. |last8=Wei |first8=S. |last9=Falck |first9=J.R. |last10=Jat |first10=J.L. |last11=Zent |first11=R. |last12=Capdevila |first12=J.H. |last13=Pozzi |first13=A. |date=2014 |title=PPARα activation can help prevent and treat non-small cell lung cancer |journal=Cancer Research |volume=74 |issue=2 |pages=62 1–631 |doi=10.1158/0008-5472.CAN-13-1928 |pmc=3902646 |pmid=24302581}} 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.{{Cite journal |last1=Sausville |first1=L.N. |last2=Gangadhariah |first2=M. |last3=Chiusa |first3=M. |last4=Mei |first4=S. |last5=Wei |first5=S. |last6=Zent |first6=R. |last7=Luther |first7=J.M. |last8=Shuey |first8=M.M. |last9=Capdevila |first9=J.H. |last10=Falck |first10=J.R. |last11=Guengerich |first11=F.P. |last12=Williams |first12=S.M. |last13=Pozzi |first13=A. |date=2018 |title=The cytochrome P450 slow metabolizers CPY2C9*2 and CYP2C9*3 directly regulate tumorigenesis via reduced epoxyeicosatrienoic acid production |journal=Cancer Research |volume=78 |issue=17 |pages=4865–4877 |doi=10.1158/0008-5472.CAN-17-3977 |pmc=6125168 |pmid=30012669}}

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.

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{{DEFAULTSORT:Capdevila, Jorge H.}}

Category:1940 births

Category:Living people

Category:20th-century American biochemists

Category:Scientists from Santiago, Chile

Category:Fellows of the American Heart Association

Category:University of Chile alumni

Category:University of Georgia alumni

Category:Vanderbilt University faculty