Skip to main content

Advertisement

SpringerLink
Log in

Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase

  • Review Article
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Xanthine oxidoreductase (XOR), the molybdoflavin enzyme responsible for the terminal steps of purine degradation in humans, is also recognized as a significant source of reactive species contributory to inflammatory disease. In animal models and clinical studies, inhibition of XOR has resulted in diminution of symptoms and enhancement of function in a number of pathologies including heart failure, diabetes, sickle cell anemia, hypertension and ischemia–reperfusion injury. For decades, XOR involvement in pathologic processes has been established by salutary outcomes attained from treatment with the XOR inhibitor allopurinol. This has served to frame a working dogma that elevation of XOR-specific activity is associated with enhanced rates of reactive species generation that mediate negative outcomes. While adherence to this narrowly focused practice of designating elevated XOR activity to be “bad” has produced some benefit, it has also led to significant underdevelopment of the processes mediating XOR regulation, identification of alternative reactants and products as well as micro-environmental factors that alter enzymatic activity. This is exemplified by recent reports: (1) identifying XOR as a nitrite reductase and thus a source of beneficial nitric oxide (•NO) under in vivo conditions similar to those where XOR inhibition has been assumed an optimal treatment choice, (2) describing XOR-derived uric acid (UA) as a critical pro-inflammatory mediator in vascular and metabolic disease and (3) ascribing an antioxidant/protective role for XOR-derived UA. When taken together, these proposed and countervailing functions of XOR affirm the need for a more comprehensive evaluation of product formation as well as the factors that govern product identity. As such, this review will critically evaluate XOR-catalyzed oxidant, •NO and UA formation as well as identify factors that mediate their production, inhibition and the resultant impact on inflammatory disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

GAGs:

Glycosaminoglycans

H2O2 :

Hydrogen peroxide

•NO:

Nitric oxide

NOS:

Nitric oxide synthase

O •−2 :

Superoxide

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

UA:

Uric acid

XDH:

Xanthine dehydrogenase

XO:

Xanthine oxidase

XOR:

Xanthine oxidoreductase

References

  • Abdulnour RE, Peng X, Finigan JH, Han EJ, Hasan EJ, Birukov KG, Reddy SP, Watkins JE 3rd, Kayyali US, Garcia JG, Tuder RM, Hassoun PM (2006) Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways. Am J Physiol Lung Cell Mol Physiol 291:L345–L353

    CAS  PubMed  Google Scholar 

  • Adachi T, Fukushima T, Usami Y, Hirano K (1993) Binding of human xanthine oxidase to sulphated glycosaminoglycans on the endothelial-cell surface. Biochem J 289:523–527

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ahmed MI, Gladden JD, Litovsky SH, Lloyd SG, Gupta H, Inusah S, Denney T Jr, Powell P, McGiffin DC, Dell’Italia LJ (2010) Increased oxidative stress and cardiomyocyte myofibrillar degeneration in patients with chronic isolated mitral regurgitation and ejection fraction > 60%. J Am Coll Cardiol 55:671–679

    CAS  PubMed Central  PubMed  Google Scholar 

  • Alef MJ, Vallabhaneni R, Carchman E, Morris SM Jr, Shiva S, Wang Y, Kelley EE, Tarpey MM, Gladwin MT, Tzeng E, Zuckerbraun BS (2011) Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats. J Clin Invest 121:1646–1656

    PubMed Central  PubMed  Google Scholar 

  • Amaya Y, Yamazaki K, Sato M, Noda K, Nishino T (1990) Proteolytic conversion of xanthine dehydrogenase from the NAD-dependent type to the O2-dependent type. Amino acid sequence of rat liver xanthine dehydrogenase and identification of the cleavage sites of the enzyme protein during irreversible conversion by trypsin. J Biol Chem 265:14170–14175

    CAS  PubMed  Google Scholar 

  • Ames BN, Cathcart R, Schwiers E, Hochstein P (1981) Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA 78:6858–6862

    CAS  PubMed Central  PubMed  Google Scholar 

  • Aroor AR, McKarns S, Demarco VG, Jia G, Sowers JR (2013) Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance. Metabolism 62:1543–1552

    CAS  PubMed  Google Scholar 

  • Aslan M, Freeman BA (2004) Oxidant-mediated impairment of nitric oxide signaling in sickle cell disease–mechanisms and consequences. Cell Mol Biol (Noisy-le-grand) 50:95–105

    CAS  Google Scholar 

  • Aslan M, Ryan TM, Adler B, Townes TM, Parks DA, Thompson JA, Tousson A, Gladwin MT, Patel RP, Tarpey MM, Batinic-Haberle I, White CR, Freeman BA (2001) Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci USA 98:15215–15220

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baker JE, Su J, Fu X, Hsu A, Gross GJ, Tweddell JS, Hogg N (2007) Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K(ATP) channels. J Mol Cell Cardiol 43:437–444

    CAS  PubMed Central  PubMed  Google Scholar 

  • Baldwin W, McRae S, Marek G, Wymer D, Pannu V, Baylis C, Johnson RJ, Sautin YY (2011) Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 60:1258–1269

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ball EG (1939) Xanthine oxidase: purification and properties. J Biol Chem 128:51–67

    CAS  Google Scholar 

  • Bentley R, Neuberger A (1952) The mechanism of the action of uricase. Biochem J 52:694–699

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bittner F, Oreb M, Mendel RR (2001) ABA3 is a molybdenum cofactor sulfurase required for activation of aldehyde oxidase and xanthine dehydrogenase in Arabidopsis thaliana. J Biol Chem 276:40381–40384

    CAS  PubMed  Google Scholar 

  • Briley MS, Eisenthal R (1974) Association of xanthine oxidase with the bovine milk-fat-globule membrane. Biochem J 143:149–157

    CAS  PubMed Central  PubMed  Google Scholar 

  • Budhiraja R, Kayyali US, Karamsetty M, Fogel M, Hill NS, Chalkley R, Finlay GA, Hassoun PM (2003) Estrogen modulates xanthine dehydrogenase/xanthine oxidase activity by a receptor-independent mechanism. Antioxid Redox Signal 5:705–711

    CAS  PubMed  Google Scholar 

  • Burian R (1905) Ueber dis oxidative und dis vermeindlich synthetische Bildung von Haurnsaure in Rinderleberauszug. Zeitsohr f Physiol Chem 43:497

    Google Scholar 

  • Butler R, Morris AD, Belch JJ, Hill A, Struthers AD (2000) Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension 35:746–751

    CAS  PubMed  Google Scholar 

  • Cantu-Medellin N, Kelley EE (2013) Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: insights regarding where, when and how. Nitric Oxide 34:19–26

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chaudhary K, Malhotra K, Sowers J, Aroor A (2013) Uric acid–key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal Med 3:208–220

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cheung KJ, Tzameli I, Pissios P, Rovira I, Gavrilova O, Ohtsubo T, Chen Z, Finkel T, Flier JS, Friedman JM (2007) Xanthine oxidoreductase is a regulator of adipogenesis and PPARgamma] activity. Cell Metab 5:115–128

    CAS  PubMed  Google Scholar 

  • Chiney MS, Schwarzenberg SJ, Johnson LA (2011) Altered xanthine oxidase and N-acetyltransferase activity in obese children. Br J Clin Pharmacol 72:109–115

    CAS  PubMed Central  PubMed  Google Scholar 

  • Clare DA, Lecce JG (1991) Copurification of bovine milk xanthine oxidase and immunoglobulin. Arch Biochem Biophys 286:233–237

    CAS  PubMed  Google Scholar 

  • Cosby K, Partovi KS, Crawford JH, Patel RP, Reiter CD, Martyr S, Yang BK, Waclawiw MA, Zalos G, Xu X, Huang KT, Shields H, Kim-Shapiro DB, Schechter AN, Cannon RO 3rd, Gladwin MT (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9:1498–1505

    CAS  PubMed  Google Scholar 

  • Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD, Kraus D, Ho C, Gladwin MT, Patel RP (2006) Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107:566–574

    CAS  PubMed Central  PubMed  Google Scholar 

  • Desco MC, Asensi M, Marquez R, Martinez-Valls J, Vento M, Pallardo FV, Sastre J, Vina J (2002) Xanthine oxidase is involved in free radical production in type 1 diabetes: protection by allopurinol. Diabetes 51:1118–1124

    CAS  PubMed  Google Scholar 

  • Dixon M, Thurlow S (1924) Studies on xanthine oxidase: preparation and properties of the active material. Biochem J 18:971–975

    CAS  PubMed Central  PubMed  Google Scholar 

  • Doel JJ, Godber BLJ, Eisenthal R, Harrison R (2001) Reduction of organic nitrates catalysed by xanthine oxidoreductase under anaerobic conditions. Biochim Biophys Acta 1527:81–87

    CAS  PubMed  Google Scholar 

  • Eddy LJ, Stewart JR, Jones HP, Engerson TD, McCord JM, Downey JM (1987) Free radical-producing enzyme, xanthine oxidase, is undetectable in human hearts. Am J Physiol Heart Circ Physiol 253:H709–H711

    CAS  Google Scholar 

  • Emerit I, Fabiani JN, Ponzio O, Murday A, Lunel F, Carpentier A (1988) Clastogenic factor in ischemia-reperfusion injury during open-heart surgery: protective effect of allopurinol. Ann Thorac Surg 46:619–624

    CAS  PubMed  Google Scholar 

  • Enroth C, Eger BT, Okamoto K, Nishino T, Nishino T, Pai EF (2000) Crystal structures of bovine milk xanthine dehydrogenase and xanthine oxidase: structure-based mechanism of conversion. Proc Natl Acad Sci USA 97:10723–10728

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fabbrini E, Serafini M, Colic Baric I, Hazen SL, Klein S (2014) Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 63:976–981

    CAS  PubMed Central  PubMed  Google Scholar 

  • Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD (2002) Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation 106:221–226

    CAS  PubMed  Google Scholar 

  • Frei B, England L, Ames BN (1989) Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci USA 86:6377–6381

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fridovich I (1970) Quantitative aspects of the production of superoxide anion radical by milk xanthine oxidase. J Biol Chem 245:4053–4057

    CAS  PubMed  Google Scholar 

  • Friedl HP, Smith DJ, Till GO, Thomson PD, Louis DS, Ward PA (1990) Ischemia-reperfusion in humans. Appearance of xanthine oxidase activity. Am J Pathol 136:491–495

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fukushima T, Adachi T, Hirano K (1995) The heparin-binding site of human xanthine oxidase. Biol Pharm Bull 18:156–158

    CAS  PubMed  Google Scholar 

  • Galbusera C, Orth P, Fedida D, Spector T (2006) Superoxide radical production by allopurinol and xanthine oxidase. Biochem Pharmacol 71:1747–1752

    CAS  PubMed  Google Scholar 

  • Gardlik S, Barber MJ, Rajagopalan KV (1987) A molybdopterin-free form of xanthine oxidase. Arch Biochem Biophys 259:363–371

    CAS  PubMed  Google Scholar 

  • Gladden JD, Zelickson BR, Wei CC, Ulasova E, Zheng J, Ahmed MI, Chen Y, Bamman M, Ballinger S, Darley-Usmar V, Dell’Italia LJ (2011) Novel insights into interactions between mitochondria and xanthine oxidase in acute cardiac volume overload. Free Radic Biol Med 51:1975–1984

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gladwin MT (2008) Evidence mounts that nitrite contributes to hypoxic vasodilation in the human circulation. Circulation 117:594–597

    PubMed  Google Scholar 

  • Gladwin MT, Raat NJH, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB, Patel RP (2006) Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 291:H2026–H2035

    CAS  PubMed  Google Scholar 

  • Godber BLJ, Doel JJ, Sapkota GP, Blake DR, Stevens CR, Eisenthal R, Harrison R (2000) Reduction of nitrite to nitric oxide catalyzed by xanthine oxidoreductase. J Biol Chem 275:7757–7763

    CAS  PubMed  Google Scholar 

  • Godber BLJ, Schwarz G, Mendel RR, Lowe DJ, Bray RC, Eisenthal R, Harrison R (2005) Molecular characterization of human xanthine oxidoreductase: the enzyme is grossly deficient in molybdenum and substantially deficient in iron-sulphur centres. Biochem J 388:501–508

    CAS  PubMed Central  PubMed  Google Scholar 

  • Granell S, Gironella M, Bulbena O, Panes J, Mauri M, Sabater L, Aparisi L, Gelpi E, Closa D (2003) Heparin mobilizes xanthine oxidase and induces lung inflammation in acute pancreatitis. Crit Care Med 31:525–530

    CAS  PubMed  Google Scholar 

  • Griguer CE, Oliva CR, Kelley EE, Giles GI, Lancaster JR Jr, Gillespie GY (2006) Xanthine oxidase-dependent regulation of hypoxia-inducible factor in cancer cells. Cancer Res 66:2257–2263

    CAS  PubMed  Google Scholar 

  • Grum CM, Ragsdale RA, Ketai LH, Shlafer M (1986) Absence of xanthine oxidase or xanthine dehydrogenase in the rabbit myocardium. Biochem Biophy Res Commun 141:1104–1108

    CAS  Google Scholar 

  • Gutteridge S, Tanner SJ, Bray RC (1978) Comparison of the molybdenum centres of native and desulpho xanthine oxidase. The nature of the cyanide-labile sulphur atom and the nature of the proton-accepting group. Biochem J 175:887–897

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hare JM, Johnson RJ (2003) Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation 107:1951–1953

    PubMed  Google Scholar 

  • Harris CM, Massey V (1997a) The reaction of reduced xanthine dehydrogenase with molecular oxygen. Reaction kinetics and measurement of the superoxide radical. J Biol Chem 272:8370–8379

    CAS  PubMed  Google Scholar 

  • Harris CM, Massey V (1997b) The oxidative half-reaction of xanthine dehydrogenase with NAD; reaction kinetics and steady-state mechanism. J Biol Chem 272:28335–28341

    CAS  PubMed  Google Scholar 

  • Hassoun PM, Yu FS, Shedd AL, Zulueta JJ, Thannickal VJ, Lanzillo JJ, Fanburg BL (1994) Regulation of endothelial cell xanthine dehydrogenase xanthine oxidase gene expression by oxygen tension. Am J Physiol Lung Cell Mol Physiol 266:L163–L171

    CAS  Google Scholar 

  • Heunks LMA, Vina J, van Herwaarden CLA, Folgering HTM, Gimeno A, Dekhuijzen PNR (1999) Xanthine oxidase is involved in exercise-induced oxidative stress in chronic obstructive pulmonary disease. Am J Physiol Regul Integr Comp Physiol 277:R1697–R1704

    CAS  Google Scholar 

  • Hille R (2002) Molybdenum and tungsten in biology. Trends Biochem Sci 27:360–367

    CAS  PubMed  Google Scholar 

  • Himmel HM, Sadony V, Ravens U (1991) Quantitation of hypoxanthine in plasma from patients with ischemic heart disease: adaption of a high-performance liquid chromatographic method. J Chromatogr 568:105–115

    CAS  PubMed  Google Scholar 

  • Hoidal JR, Xu P, Huecksteadt T, Sanders KA, Pfeffer K (1997) Transcriptional regulation of human xanthine dehydrogenase/xanthine oxidase. Biochem Soc Trans 25:796–799

    CAS  PubMed  Google Scholar 

  • Houston M, Estevez A, Chumley P, Aslan M, Marklund S, Parks DA, Freeman BA (1999) Binding of xanthine oxidase to vascular endothelium. Kinetic characterization and oxidative impairment of nitric oxide-dependent signaling. J Biol Chem 274:4985–4994

    CAS  PubMed  Google Scholar 

  • Huang Z, Shiva S, Kim-Shapiro DB, Patel RP, Ringwood LA, Irby CE, Huang KT, Ho C, Hogg N, Schechter AN, Gladwin MT (2005) Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. J Clin Invest 115:2099–2107

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang L, Borniquel S, Lundberg JO (2010) Enhanced xanthine oxidoreductase expression and tissue nitrate reduction in germ free mice. Nitric Oxide 22:191–195

    CAS  PubMed  Google Scholar 

  • Hunt J, Massey V, Dunham WR, Sands RH (1993) Redox potentials of milk xanthine dehydrogenase. Room temperature measurement of the FAD and 2Fe/2S center potentials. J Biol Chem 268:18685–18691

    CAS  PubMed  Google Scholar 

  • Ichida K, Matsumura T, Sakuma R, Hosoya T, Nishino T (2001) Mutation of human molybdenum cofactor sulfurase gene is responsible for classical xanthinuria type II. Biochem Biophys Res Commun 282:1194–1200

    CAS  PubMed  Google Scholar 

  • Iwasaki T, Okamoto K, Nishino T, Mizushima J, Hori H (2000) Sequence motif-specific assignment of two [2Fe–2S] clusters in rat xanthine oxidoreductase studied by site-directed mutagenesis. J Biochem 127:771–778

    CAS  PubMed  Google Scholar 

  • Jia G, Aroor AR, Whaley-Connell AT, Sowers JR (2014) Fructose and uric acid: is there a role in endothelial function? Curr Hypertens Rep 16:434

    PubMed Central  PubMed  Google Scholar 

  • Kayyali US, Donaldson C, Huang H, Abdelnour R, Hassoun PM (2001) Phosphorylation of xanthine dehydrogenase/oxidase in hypoxia. J Biol Chem 276:14359–14365

    CAS  PubMed  Google Scholar 

  • Kelley EE, Trostchansky A, Rubbo H, Freeman BA, Radi R, Tarpey MM (2004) Binding of xanthine oxidase to glycosaminoglycans limits inhibition by oxypurinol. J Biol Chem 279:37231–37234

    CAS  PubMed  Google Scholar 

  • Kelley EE, Hock T, Khoo NK, Richardson GR, Johnson KK, Powell PC, Giles GI, Agarwal A, Lancaster JR Jr, Tarpey MM (2006) Moderate hypoxia induces xanthine oxidoreductase activity in arterial endothelial cells. Free Radic Biol Med 40:952–959

    CAS  PubMed  Google Scholar 

  • Kelley EE, Khoo NK, Hundley NJ, Malik UZ, Freeman BA, Tarpey MM (2010) Hydrogen peroxide is the major oxidant product of xanthine oxidase. Free Radic Biol Med 48:493–498

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim NH, Choi S, Han EJ, Hong BK, Choi SY, Kwon HM, Hwang SY, Cho CS, Kim WU (2014) The xanthine oxidase-NFAT5 pathway regulates macrophage activation and TLR-induced inflammatory arthritis. Eur J Immunol 44:2721–2736

    CAS  PubMed  Google Scholar 

  • Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O, Scheeren T, Godecke A, Schrader J, Schulz R, Heusch G, Schaub GA, Bryan NS, Feelisch M, Kelm M (2003) Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 35:790–796

    CAS  PubMed  Google Scholar 

  • Kooij A (1994) A re-evaluation of the tissue distribution and physiology of xanthine oxidoreductase. Histochem J 26:889–915

    CAS  PubMed  Google Scholar 

  • Kooy NW, Royall JA, Ischiropoulos H (1997) Oxidation of 2′,7′-dichlorofluorescin by peroxynitrite. Free Radic Res 27:245–254

    CAS  PubMed  Google Scholar 

  • Kundu TK, Velayutham M, Zweier JL (2012) Aldehyde oxidase functions as a superoxide generating NADH oxidase: an important redox regulated pathway of cellular oxygen radical formation. Biochemistry 51:2930–2939

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kuwabara Y, Nishino T, Okamoto K, Matsumura T, Eger BT, Pai EF, Nishino T (2003) Unique amino acids cluster for switching from the dehydrogenase to oxidase form of xanthine oxidoreductase. Proc Natl Acad Sci USA 100:8170–8175

    CAS  PubMed Central  PubMed  Google Scholar 

  • Landmesser U, Spiekermann S, Dikalov S, Tatge H, Wilke R, Kohler C, Harrison DG, Hornig B, Drexler H (2002) Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular superoxide dismutase. Circulation 106:3073–3078

    CAS  PubMed  Google Scholar 

  • Lartigue-Mattei C, Chabard JL, Bargnoux H, Petit J, Berger JA, Ristori JM, Bussiere JL, Catilina P, Catilina MJ (1990) Plasma and blood assay of xanthine and hypoxanthine by gas chromatography-mass spectrometry: physiological variations in humans. J Chromatogr 529:93–101

    CAS  PubMed  Google Scholar 

  • Li H, Samouilov A, Liu X, Zweier JL (2001) Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrite reduction: evaluation of its role in nitric oxide generation in anoxic tissues. J Biol Chem 276:24482–24489

    CAS  PubMed  Google Scholar 

  • Li H, Samouilov A, Liu X, Zweier JL (2004) Characterization of the effects of oxygen on xanthine oxidase-mediated nitric oxide formation. J Biol Chem 279:16939–16946

    CAS  PubMed  Google Scholar 

  • Li H, Cui H, Liu X, Zweier JL (2005) Xanthine oxidase catalyzes anaerobic transformation of organic nitrates to nitric oxide and nitrosothiols: characterization of this mechanism and the link between organic nitrate and guanylyl cyclase activation. J Biol Chem 280:16594–16600

    CAS  PubMed  Google Scholar 

  • Li H, Cui H, Kundu TK, Alzawahra W, Zweier JL (2008) Nitric oxide production from nitrite occurs primarily in tissues not in the blood: critical role of xanthine oxidase and aldehyde oxidase. J Biol Chem 283:17855–17863

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li H, Kundu TK, Zweier JL (2009) Characterization of the magnitude and mechanism of aldehyde oxidase-mediated nitric oxide production from nitrite. J Biol Chem 284:33850–33858

    CAS  PubMed Central  PubMed  Google Scholar 

  • Linder N, Martelin E, Lapatto R, Raivio KO (2003) Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions. Am J Physiol Cell Physiol 285:C48–C55

    CAS  PubMed  Google Scholar 

  • Lu P, Liu F, Yao Z, Wang CY, Chen DD, Tian Y, Zhang JH, Wu YH (2005) Nitrite-derived nitric oxide by xanthine oxidoreductase protects the liver against ischemia-reperfusion injury. Hepatobiliary Pancreat Dis Int 4:350–355

    CAS  PubMed  Google Scholar 

  • Lundberg JO, Weitzberg E (2005) NO Generation From Nitrite and Its Role in Vascular Control. Arterioscler Thromb Vasc Biol 25:915–922

    CAS  PubMed  Google Scholar 

  • Malik UZ, Hundley NJ, Romero G, Radi R, Freeman BA, Tarpey MM, Kelley EE (2011) Febuxostat inhibition of endothelial-bound XO: implications for targeting vascular ROS production. Free Radic Biol Med 51:179–184

    CAS  PubMed Central  PubMed  Google Scholar 

  • Martelin E, Palvimo JJ, Lapatto R, Raivio KO (2000) Nuclear factor Y activates the human xanthine oxidoreductase gene promoter. FEBS Lett 480:84–88

    CAS  PubMed  Google Scholar 

  • Massey V, Harris CM (1997) Milk xanthine oxidoreductase: the first one hundred years. Biochem Soc Trans 25:750–755

    CAS  PubMed  Google Scholar 

  • Massey V, Komai H, Palmer G, Elion GB (1970) On the mechanism of inactivation of xanthine oxidase by allopurinol and other pyrazolo[3,4-d]pyrimidines. J Biol Chem 245:2837–2844

    CAS  PubMed  Google Scholar 

  • Masuo K, Kawaguchi H, Mikami H, Ogihara T, Tuck ML (2003) Serum uric acid and plasma norepinephrine concentrations predict subsequent weight gain and blood pressure elevation. Hypertension 42:474–480

    CAS  PubMed  Google Scholar 

  • McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055

    CAS  PubMed  Google Scholar 

  • Millar TM (2004) Peroxynitrite formation from the simultaneous reduction of nitrite and oxygen by xanthine oxidase. FEBS Lett 562:129–133

    CAS  PubMed  Google Scholar 

  • Millar TM, Stevens CR, Benjamin N, Eisenthal R, Harrison R, Blake DR (1998) Xanthine oxidoreductase catalyses the reduction of nitrates and nitrite to nitric oxide under hypoxic conditions. FEBS Lett 427:225–228

    CAS  PubMed  Google Scholar 

  • Morgan EJ, Stewart CP, Hopkins FG (1922) On the anaerobic and aerobic oxidation of xanthin and hypoxanthin by tissues and milk. Proc R Soc Lond Ser B 94:109–131

    Google Scholar 

  • Murakami N, Ohtsubo T, Kansui Y, Goto K, Noguchi H, Haga Y, Nakabeppu Y, Matsumura K, Kitazono T (2014) Mice heterozygous for the xanthine oxidoreductase gene facilitate lipid accumulation in adipocytes. Arterioscler Thromb Vasc Biol 34:44–51

    CAS  PubMed  Google Scholar 

  • Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ (2006) A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290:F625–F631

    CAS  PubMed  Google Scholar 

  • Nanduri J, Vaddi DR, Khan SA, Wang N, Makerenko V, Prabhakar NR (2013) Xanthine oxidase mediates hypoxia-inducible factor-2alpha degradation by intermittent hypoxia. PLoS ONE 8:e75838

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nanduri J, Vaddi DR, Khan SA, Wang N, Makarenko V, Semenza GL, Prabhakar NR (2015) HIF-1alpha activation by intermittent hypoxia requires NADPH oxidase stimulation by xanthine oxidase. PLoS ONE 10:e0119762

    PubMed Central  PubMed  Google Scholar 

  • Nishino T, Okamoto K (2000) The role of the [2Fe–2 s] cluster centers in xanthine oxidoreductase. J Inorg Biochem 82:43–49

    CAS  PubMed  Google Scholar 

  • Ohtsubo T, Rovira II, Starost MF, Liu C, Finkel T (2004) Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2. Circ Res 95:1118–1124

    CAS  PubMed  Google Scholar 

  • Okamoto K, Nishino T (2008) Crystal structures of mammalian xanthine oxidoreductase bound with various inhibitors: allopurinol, febuxostat, and FYX-051. J Nippon Med Sch 75:2–3

    PubMed  Google Scholar 

  • Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF (2003) An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem 278:1848–1855

    CAS  PubMed  Google Scholar 

  • Olson JS, Ballow DP, Palmer G, Massey V (1974) The reaction of xanthine oxidase with molecular oxygen. J Biol Chem 249:4350–4362

    CAS  PubMed  Google Scholar 

  • Pacher P, Nivorozhkin A, Szabo C (2006) Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacol Rev 58:87–114

    CAS  PubMed Central  PubMed  Google Scholar 

  • Page S, Powell D, Benboubetra M, Stevens CR, Blake DR, Selase F, Wolstenholme AJ, Harrison R (1998) Xanthine oxidoreductase in human mammary epithelial cells: activation in response to inflammatory cytokines. Biochim Biophys Acta 1381:191–202

    CAS  PubMed  Google Scholar 

  • Parks DA, Bulkley GB, Granger DN, Hamilton SR, McCord JM (1982) Ischemic injury in the cat small intestine: role of superoxide radicals. Gastroenterology 82:9–15

    CAS  PubMed  Google Scholar 

  • Parks DA, Williams TK, Beckman JS (1988) Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: a reevaluation. Am J Physiol 254:G768–G774

    CAS  PubMed  Google Scholar 

  • Partridge CA, Blumenstock FA, Malik AB (1992) Pulmonary microvascular endothelial cells constitutively release xanthine oxidase. Arch Biochem Biophys 294:184–187

    CAS  PubMed  Google Scholar 

  • Pesonen EJ, Linder N, Raivio KO, Sarnesto A, Lapatto R, Hockerstedt K, Makisalo H, Andersson S (1998) Circulating xanthine oxidase and neutrophil activation during human liver transplantation. Gastroenterology 114:1009–1015

    CAS  PubMed  Google Scholar 

  • Pickerodt PA, Emery MJ, Zarndt R, Martin W, Francis RC, Boemke W, Swenson ER (2012) Sodium nitrite mitigates ventilator-induced lung injury in rats. Anesthesiology 117:592–601

    CAS  PubMed  Google Scholar 

  • Poss WB, Huecksteadt TP, Panus PC, Freeman BA, Hoidal JR (1996) Regulation of xanthine dehydrogenase and xanthine oxidase activity by hypoxia. Am J Physiol Lung Cell Mol Physiol 270:L941–L946

    CAS  Google Scholar 

  • Quinlan GJ, Lamb NJ, Tilley R, Evans TW, Gutteridge JM (1997) Plasma hypoxanthine levels in ARDS: implications for oxidative stress, morbidity, and mortality. Am J Respir Crit Care Med 155:479–484

    CAS  PubMed  Google Scholar 

  • Radi R, Rubbo H, Bush K, Freeman BA (1997) Xanthine oxidase binding to glycosaminoglycans: kinetics and superoxide dismutase interactions of immobilized xanthine oxidase-heparin complexes. Arch Biochem Biophys 339:125–135

    CAS  PubMed  Google Scholar 

  • Rajesh M, Mukhopadhyay P, Batkai S, Mukhopadhyay B, Patel V, Hasko G, Szabo C, Mabley JG, Liaudet L, Pacher P (2009) Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. J Cell Mol Med 13:2330–2341

    PubMed Central  PubMed  Google Scholar 

  • Samal AA, Honavar J, Brandon A, Bradley KM, Doran S, Liu Y, Dunaway C, Steele C, Postlethwait EM, Squadrito GL, Fanucchi MV, Matalon S, Patel RP (2012) Administration of nitrite after chlorine gas exposure prevents lung injury: effect of administration modality. Free Radic Biol Med 53:1431–1439

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sarnesto A, Linder N, Raivio KO (1996) Organ distribution and molecular forms of human xanthine dehydrogenase/xanthine oxidase protein. Lab Invest 74:48–56

    CAS  PubMed  Google Scholar 

  • Schroder K, Vecchione C, Jung O, Schreiber JG, Shiri-Sverdlov R, van Gorp PJ, Busse R, Brandes RP (2006) Xanthine oxidase inhibitor tungsten prevents the development of atherosclerosis in ApoE knockout mice fed a Western-type diet. Free Radic Biol Med 41:1353–1360

    PubMed  Google Scholar 

  • Shardinger FZ (1902) Uber das verhalten der kulmilch gegen methylenblau und seine verwendung zur unterscheidung von ungekochter und gekochter milch. Utersuch Nahrungs- u Genussmittel 5:1113–1121

    Google Scholar 

  • Soltani Z, Rasheed K, Kapusta DR, Reisin E (2013) Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal? Curr Hypertens Rep 15:175–181

    CAS  PubMed Central  PubMed  Google Scholar 

  • Spitzer W (1899) Die Ueberführung von Nucleïnbasen in Harnsäure durch die sauerstoffübertragende Wirkung von Gewebsauszügen. Arch Ges Physiol 76:192–203

    Google Scholar 

  • Stone JR, Yang S (2006) Hydrogen peroxide: a signaling messenger. Antioxid Redox Signal 8:243–270

    CAS  PubMed  Google Scholar 

  • Sugimoto R, Okamoto T, Nakao A, Zhan J, Wang Y, Kohmoto J, Tokita D, Farver CF, Tarpey MM, Billiar TR, Gladwin MT, McCurry KR (2012) Nitrite reduces acute lung injury and improves survival in a rat lung transplantation model. Am J Transplant 12:2938–2948

    CAS  PubMed  Google Scholar 

  • Takano Y, Hase-Aoki K, Horiuchi H, Zhao L, Kasahara Y, Kondo S, Becker MA (2005) Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci 76:1835–1847

    CAS  PubMed  Google Scholar 

  • Tam HK, Kelly AS, Metzig AM, Steinberger J, Johnson LA (2014) Xanthine oxidase and cardiovascular risk in obese children. Child Obes 10:175–180

    PubMed Central  PubMed  Google Scholar 

  • Tamariz L, Hernandez F, Bush A, Palacio A, Hare JM (2014) Association between serum uric acid and atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm 11:1102–1108

    PubMed  Google Scholar 

  • Tan S, Gelman S, Wheat JK, Parks DA (1995) Circulating xanthine oxidase in human ischemia reperfusion. South Med J 88:479–482

    CAS  PubMed  Google Scholar 

  • Terada LS, Beehler CJ, Banerjee A, Brown JM, Grosso MA, Harken AH, McCord JM, Repine JE (1988) Hyperoxia and self- or neutrophil-generated O2 metabolites inactivate xanthine oxidase. J Appl Physiol 65:2349–2353

    CAS  PubMed  Google Scholar 

  • Terada LS, Guidot DM, Leff JA, Willingham IR, Hanley ME, Piermattei D, Repine JE (1992) Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci 89:3362–3366

    CAS  PubMed Central  PubMed  Google Scholar 

  • Terada LS, Piermattei D, Shibao GN, McManaman JL, Wright RM (1997) Hypoxia regulates xanthine dehydrogenase activity at pre- and posttranslational levels. Arch Biochem Biophys 348:163–168

    CAS  PubMed  Google Scholar 

  • Tripatara P, Patel NS, Webb A, Rathod K, Lecomte FM, Mazzon E, Cuzzocrea S, Yaqoob MM, Ahluwalia A, Thiemermann C (2007) Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase. J Am Soc Nephrol 18:570–580

    CAS  PubMed  Google Scholar 

  • Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26:1–14

    CAS  PubMed  Google Scholar 

  • Vorbach C, Scriven A, Capecchi MR (2002) The housekeeping gene xanthine oxidoreductase is necessary for milk fat droplet enveloping and secretion: gene sharing in the lactating mammary gland. Genes Dev 16:3223–3235

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wagner JR, Motchnik PA, Stocker R, Sies H, Ames BN (1993) The oxidation of blood plasma and low density lipoprotein components by chemically generated singlet oxygen. J Biol Chem 268:18502–18506

    CAS  PubMed  Google Scholar 

  • Wang J, Krizowski S, Fischer-Schrader K, Niks D, Tejero J, Sparacino-Watkins C, Wang L, Ragireddy V, Frizzell S, Kelley EE, Zhang Y, Basu P, Hille R, Schwarz G, Gladwin MT (2014) Sulfite oxidase catalyzes single-electron transfer at molybdenum domain to reduce nitrite to nitric oxide. Antioxid Redox Signal

  • Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A (2004) Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 101:13683–13688

    CAS  PubMed Central  PubMed  Google Scholar 

  • Weidert ER, Schoenborn SO, Cantu-Medline N, Choughoule KV, Jones JP, Kelley EE (2014) Inhibition of xanthine oxidase by the aldehyde oxidase inhibitor raloxifene: implications for identifying molybdopterin nitrite reductases. Nitric Oxide 37:41–45

    CAS  PubMed Central  PubMed  Google Scholar 

  • White CR, Darley-Usmar V, Berrington WR, McAdams M, Gore JZ, Thompson JA, Parks DA, Tarpey MM, Freeman BA (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci USA 93:8745–8749

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wright RM, Ginger LA, Kosila N, Elkins ND, Essary B, McManaman JL, Repine JE (2004) Mononuclear phagocyte xanthine oxidoreductase contributes to cytokine-induced acute lung injury. Am J Respir Cell Mol Biol 30:479–490

    CAS  PubMed  Google Scholar 

  • Wu X, Wakamiya M, Vaishnav S, Geske R, Montgomery C Jr, Jones P, Bradley A, Caskey CT (1994) Hyperuricemia and urate nephropathy in urate oxidase-deficient mice. Proc Natl Acad Sci USA 91:742–746

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yokoyama Y, Beckman JS, Beckman TK, Wheat JK, Cash TG, Freeman BA, Parks DA (1990) Circulating xanthine oxidase: potential mediator of ischemic injury. Am J Physiol Gastrointest Liver Physiol 258:G564–G570

    CAS  Google Scholar 

  • Zhang JX, Zhang YP, Wu QN, Chen B (2014) Uric acid induces oxidative stress via an activation of the renin-angiotensin system in 3T3-L1 adipocytes. Endocrine 48:135–142

    PubMed  Google Scholar 

  • Zhang YS, Liu B, Luo XJ, Zhang JJ, Li NS, Ma QL, Jiang JL, Li YJ, Li Q, Peng J (2015) A novel function of nuclear nonmuscle myosin regulatory light chain in promotion of xanthine oxidase transcription after myocardial ischemia/reperfusion. Free Radic Biol Med 83:115–128

    CAS  PubMed  Google Scholar 

  • Zhao G, Huang L, Song M, Song Y (2013) Baseline serum uric acid level as a predictor of cardiovascular disease related mortality and all-cause mortality: a meta-analysis of prospective studies. Atherosclerosis 231:61–68

    CAS  PubMed  Google Scholar 

  • Zhou L, Stanley WC, Saidel GM, Yu X, Cabrera ME (2005) Regulation of lactate production at the onset of ischaemia is independent of mitochondrial NADH/NAD + : insights from in silico studies. J Physiol 569:925–937

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zuckerbraun BS, Shiva S, Ifedigbo E, Mathier MA, Mollen KP, Rao J, Bauer PM, Choi JJ, Curtis E, Choi AM, Gladwin MT (2010) Nitrite potently inhibits hypoxic and inflammatory pulmonary arterial hypertension and smooth muscle proliferation via xanthine oxidoreductase-dependent nitric oxide generation. Circulation 121:98–109

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institute on Aging, NIH 3P01AG043376-02S1 and by the University of Pittsburgh, Department of Anesthesiology.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Vascular Medicine Institute, School of Medicine, University of Pittsburgh, W1357 BST, 200 Lothrop Street, Pittsburgh, PA, 15213, USA

    Eric E. Kelley

Authors
  1. Eric E. Kelley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric E. Kelley.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kelley, E.E. Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase. Arch Toxicol 89, 1193–1207 (2015). https://doi.org/10.1007/s00204-015-1523-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-015-1523-8

Keywords

Search

Navigation