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Gene Review

XDH  -  xanthine dehydrogenase

Homo sapiens

Synonyms: XDHA, XO, XOR, Xanthine dehydrogenase/oxidase
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Disease relevance of XDH

  • Increased maternal-fetal plasma XO and ADA activities, as a marker of immunological disorder, may be related to the pathogenesis of pre-eclampsia [1].
  • Xanthine dehydrogenase (XDH, EC is a rate-limiting enzyme in the oxidative metabolism of purines and is thought to play a key role in a variety of pathophysiologic processes including ischemiasolidusreperfusion injury, viral pneumonia, and renal failure [2].
  • Moreover, in liver disease, proliferating bile ducts are also strongly positive for XOR [3].
  • XOR promoter constructs failed to respond to hypoxia [4].
  • XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure [5].

Psychiatry related information on XDH

  • Reinforcement schedules in the experiments were equivalent either to an AND rule or to an XOR rule [6].
  • Neither gender nor smoking-related differences influenced XO activity but the difference in activity between Ethiopians living in Sweden or in Ethiopia indicates influence of other environmental factors such as dietary habits on XO activity [7].
  • ELM, a patient with category-specific visual agnosia, was tested on a single-dimension categorization problem, and the "exclusive or" (XOR) categorization problem [8].
  • Although XO deficiency is relatively benign, patients with isolated deficiencies of SO or molybdenum cofactor exhibit mental retardation, neurologic problems, and ocular lens dislocation [9].
  • Based on the examination of the dependence of XOR activity on added amounts of xanthine and reaction times, the amount of xanthine and reaction time for XOR activity assay were determined to prevent the errors caused by the limiting effect of substrates and plateau phase of the reaction [10].

High impact information on XDH

  • The primary source of superoxide in reperfused reoxygenated tissues appears to be the enzyme xanthine oxidase, released during ischemia by a calcium-triggered proteolytic attack on xanthine dehydrogenase [11].
  • The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades [12].
  • Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism occurring in most cell types [13].
  • The above observations suggest that human females suffering from xanthinuria, a deficiency in XOR, are potential candidates for lactation problems [13].
  • Histological and whole-mount analyses showed that in XOR+/- females the mammary epithelium collapses, resulting in premature involution of the mammary gland [13].

Chemical compound and disease context of XDH

  • The aim of this study was to evaluate maternal-fetal plasma adenosine deaminase, xanthine oxidase (ADA, XO) activity and malondialdehyde (MDA) levels and the relationship between them in pre-eclampsia [1].
  • We conclude that the transcription or translation of XOR is not influenced by hypoxia or hyperoxia [4].
  • Xanthine oxidoreductase (XOR) catalyzes the final reactions of purine catabolism and may account for cell damage by producing reactive oxygen metabolites in cells reoxygenated after hypoxia [4].
  • The enzyme complex exists in separate but interconvertible forms, xanthine dehydrogenase and xanthine oxidase, which generate reactive oxygen species (ROS), a well known causative factor in ischemia/reperfusion injury and also in some other pathological states and diseases [14].
  • These results demonstrate that febuxostat is a potent non-purine, selective inhibitor of XO, and could be useful for the treatment of hyperuricemia and gout [15].

Biological context of XDH

  • The assignment of the XDH gene to chromosome 2 at band p22 was established by fluorescence in situ hybridization on human metaphase chromosomes using a clone from a pWE 15 cosmid library containing the XDH gene [16].
  • A Version 3.0 human-hamster somatic cell hybrid PCRable DNA panel and specific PCR primers derived from human XDH cDNA for amplification were used to assign the XDH gene to human chromosome 2 [16].
  • We obtained cDNA clones from a human breast cDNA library and confirmed one of the two different sequences proposed for human XDH [17].
  • XOR mRNA levels started to increase at mid-pregnancy, turned sharply upwards at the onset of lactation and decreased rapidly with forced involution, indicating transcriptional control of the enzyme level by differentiation and secretory function [18].
  • Significant XDH/XO enzyme activity (277 +/- 54 pmol/min per mg of protein) was measured in lysates of transfected COS cells, whereas in control transfections the activities were below the detection limit of our assay (0.2 pmol/min per mg of protein) [19].

Anatomical context of XDH

  • RESULTS: There was a remarkable increase in AD activity and moderate increase in XO in patients with BD compared to controls indicating T cell activation and increased maturation [20].
  • The assignment of the N-terminal was confirmed by directly sequencing that region of purified human milk XDH [21].
  • The duodenal mucosa from the subject had no xanthine dehydrogenase protein while the mRNA level was not reduced [22].
  • However, the novel finding of this study is that XOR is present in bile duct epithelial cells, where it is concentrated toward the luminal surface [3].
  • As shown previously, XOR is present in hepatocytes [3].

Associations of XDH with chemical compounds


Regulatory relationships of XDH

  • A working model is presented to account for the role of DNA-PK and AREB6-like proteins in regulating hXOR activity [24].
  • Monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD (xanthine dehydrogenase) to XO induced by PMA-activated neutrophils [25].

Other interactions of XDH

  • Increased ADA and decreased XO, SOD, and CAT activities were found in cancerous bladder tissues compared with those of cancer-free adjacent tissues and of control bladder tissues [26].
  • Results suggest that ADA and 5'NT activities increase but XO activity decreases in cancerous human colon tissues, which may provide advantage to the cancerous tissues in obtaining new nucleotides for rapid DNA synthesis through accelerated salvage pathway activity [27].
  • The functional loss of Ku86 increases hXOR promoter activity and transcript expression [24].
  • We also included discovery of polymorphic forms of genes that code for enzymes that are inhibited by tungsten: xanthine dehydrogenase, sulfite oxidase (SUOXgene), and aldehyde oxidase [28].
  • In omega-3 FA treated rats, prefrontal tissue MDA, PC and NO levels as well as SOD, GSH-Px, XO, and AD enzyme activities were significantly decreased when compared to MK-801 groups (P<0.0001) whereas catalase (CAT) enzyme activity was not changed [29].

Analytical, diagnostic and therapeutic context of XDH

  • Significant positive correlation was found between AD and XO in BD, although there was no correlation in control group [20].
  • Northern blot analysis shows that the human XDH gene is widely expressed in human tissues [21].
  • Size-exclusion chromatography of solubilized milk fat globule membrane proteins showed that XOR formed a sulphydryl-bond-dependent complex with Btn and ADPH in the milk fat globule membrane [18].
  • The primary structure of human xanthine dehydrogenase (hXDH) was determined by cloning and sequence analysis of the cDNAs encoding the enzyme [30].
  • Instead, the molybdenum center of XOR is posttranslationally inactivated by oxygen metabolites in "normal" (21% O2) cell culture atmosphere [4].


  1. Maternal and fetal plasma adenosine deaminase, xanthine oxidase and malondialdehyde levels in pre-eclampsia. Karabulut, A.B., Kafkasli, A., Burak, F., Gozukara, E.M. Cell Biochem. Funct. (2005) [Pubmed]
  2. Molecular cloning and characterization of the human xanthine dehydrogenase gene (XDH). Xu, P., Huecksteadt, T.P., Hoidal, J.R. Genomics (1996) [Pubmed]
  3. Xanthine oxidoreductase is present in bile ducts of normal and cirrhotic liver. Martin, H.M., Moore, K.P., Bosmans, E., Davies, S., Burroughs, A.K., Dhillon, A.P., Tosh, D., Harrison, R. Free Radic. Biol. Med. (2004) [Pubmed]
  4. Posttranslational inactivation of human xanthine oxidoreductase by oxygen under standard cell culture conditions. Linder, N., Martelin, E., Lapatto, R., Raivio, K.O. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  5. The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction. Meneshian, A., Bulkley, G.B. Microcirculation (New York, N.Y. : 1994) (2002) [Pubmed]
  6. Responding under time pressure: testing two animal learning models and a model of visual categorization. Kinder, A., Lachnit, H. The Quarterly journal of experimental psychology. A, Human experimental psychology. (2002) [Pubmed]
  7. Xanthine oxidase activity is influenced by environmental factors in Ethiopians. Aklillu, E., Carrillo, J.A., Makonnen, E., Bertilsson, L., Ingelman-Sundberg, M. Eur. J. Clin. Pharmacol. (2003) [Pubmed]
  8. Superior single dimension relative to "exclusive or" categorization performance by a patient with category-specific visual agnosia: empirical data and an ALCOVE simulation. Dixon, M.J., Koehler, D., Schweizer, T.A., Guylee, M.J. Brain and cognition. (2000) [Pubmed]
  9. Molybdenum: an essential trace element. Sardesai, V.M. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. (1993) [Pubmed]
  10. Improved method for measurement of human plasma xanthine oxidoreductase activity. Liu, X., Lin, W.M., Yan, X.H., Chen, X.H., Hoidal, J.R., Xu, P. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2003) [Pubmed]
  11. Oxygen-derived free radicals in postischemic tissue injury. McCord, J.M. N. Engl. J. Med. (1985) [Pubmed]
  12. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pacher, P., Nivorozhkin, A., Szabó, C. Pharmacol. Rev. (2006) [Pubmed]
  13. The housekeeping gene xanthine oxidoreductase is necessary for milk fat droplet enveloping and secretion: gene sharing in the lactating mammary gland. Vorbach, C., Scriven, A., Capecchi, M.R. Genes Dev. (2002) [Pubmed]
  14. Xanthine oxidoreductase and xanthine oxidase in human cornea. Cejková, J., Ardan, T., Filipec, M., Midelfart, A. Histol. Histopathol. (2002) [Pubmed]
  15. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Takano, Y., Hase-Aoki, K., Horiuchi, H., Zhao, L., Kasahara, Y., Kondo, S., Becker, M.A. Life Sci. (2005) [Pubmed]
  16. Assignment of human xanthine dehydrogenase gene to chromosome 2p22. Xu, P., Zhu, X.L., Huecksteadt, T.P., Brothman, A.R., Hoidal, J.R. Genomics (1994) [Pubmed]
  17. The human gene for xanthine dehydrogenase (XDH) is localized on chromosome band 2q22. Rytkönen, E.M., Halila, R., Laan, M., Saksela, M., Kallioniemi, O.P., Palotie, A., Raivio, K.O. Cytogenet. Cell Genet. (1995) [Pubmed]
  18. Functional regulation of xanthine oxidoreductase expression and localization in the mouse mammary gland: evidence of a role in lipid secretion. McManaman, J.L., Palmer, C.A., Wright, R.M., Neville, M.C. J. Physiol. (Lond.) (2002) [Pubmed]
  19. Cloning and expression in vitro of human xanthine dehydrogenase/oxidase. Saksela, M., Raivio, K.O. Biochem. J. (1996) [Pubmed]
  20. The activities of serum adenosine deaminase and xanthine oxidase enzymes in Behcet's disease. Sögüt, S., Aydin, E., Elyas, H., Aksoy, N., Ozyurt, H., Totan, Y., Akyol, O. Clin. Chim. Acta (2002) [Pubmed]
  21. Molecular cloning, tissue expression of human xanthine dehydrogenase. Xu, P., Huecksteadt, T.P., Harrison, R., Hoidal, J.R. Biochem. Biophys. Res. Commun. (1994) [Pubmed]
  22. Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. Ichida, K., Amaya, Y., Kamatani, N., Nishino, T., Hosoya, T., Sakai, O. J. Clin. Invest. (1997) [Pubmed]
  23. Xanthine oxidase/dehydrogenase is present in human placenta. Many, A., Westerhausen-Larson, A., Kanbour-Shakir, A., Roberts, J.M. Placenta (1996) [Pubmed]
  24. Characterization of proteins binding to E-box/Ku86 sites and function of Ku86 in transcriptional regulation of the human xanthine oxidoreductase gene. Xu, P., LaVallee, P.A., Lin, J.J., Hoidal, J.R. J. Biol. Chem. (2004) [Pubmed]
  25. Cell adhesion molecule mediates endothelial cell injury caused by activated neutrophils. Murota, S., Fujita, H., Wakabayashi, Y., Morita, I. The Keio journal of medicine. (1996) [Pubmed]
  26. Adenosine deaminase, 5'nucleotidase, xanthine oxidase, superoxide dismutase, and catalase activities in cancerous and noncancerous human bladder tissues. Durak, I., Perk, H., Kavutçu, M., Canbolat, O., Akyol, O., Bedük, Y. Free Radic. Biol. Med. (1994) [Pubmed]
  27. Effects of black grape extract on activities of DNA turn-over enzymes in cancerous and non cancerous human colon tissues. Durak, I., Cetin, R., Devrim, E., Ergüder, I.B. Life Sci. (2005) [Pubmed]
  28. Genetic studies of a cluster of acute lymphoblastic leukemia cases in Churchill County, Nevada. Steinberg, K.K., Relling, M.V., Gallagher, M.L., Greene, C.N., Rubin, C.S., French, D., Holmes, A.K., Carroll, W.L., Koontz, D.A., Sampson, E.J., Satten, G.A. Environ. Health Perspect. (2007) [Pubmed]
  29. The protective effects of omega-3 fatty acids against MK-801-induced neurotoxicity in prefrontal cortex of rat. Ozyurt, B., Sarsilmaz, M., Akpolat, N., Ozyurt, H., Akyol, O., Herken, H., Kus, I. Neurochem. Int. (2007) [Pubmed]
  30. Cloning of the cDNA encoding human xanthine dehydrogenase (oxidase): structural analysis of the protein and chromosomal location of the gene. Ichida, K., Amaya, Y., Noda, K., Minoshima, S., Hosoya, T., Sakai, O., Shimizu, N., Nishino, T. Gene (1993) [Pubmed]
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