Estrogen Modulates Xanthine Dehydrogenase/Xanthine Oxidase Activity by a Receptor-Independent Mechanism

Rohit Budhiraja, Usamah S. Kayyali, Mallik Karamsetty, Michael Fogel, Nicholas S. Hill, Roger Chalkley, Geraldine A. Finlay, Paul M. Hassoun

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Hypoxia Causes Up-regulation and activation of xanthine dehydrogenase/xanthine oxidase (XDH/XO) in vitro and in the lungs in vivo. This up-regulation, and the likely corresponding production of reactive oxygen species, may underlie the pathogenesis of an array of disorders. Thus, compounds that prevent hypoxia-induced increase in XDH/XO activity may provide a therapeutic strategy in such disorders. The antioxidant properties of estrogens have been demonstrated in several studies. However, the effect of these compounds on XDH/XO has not been explored previously. The aim of this study was to investigate the effects of estrogen on hypoxia-induced increase in XDH/XO activity. Rat pulmonary artery microvascular endothelial cells were exposed to normoxia or hypoxia in the presence or absence of 17β- or 17α-estradiol. The XDH/XO enzyme and gene promoter activities were measured in different groups of cells. Hypoxia caused a twofold increase in XDH/XO enzymatic and promoter activity. Either of the estradiol stereoisomers prevented the hypoxia-induced increase in XDH/XO enzymatic activity, but not the promoter activity. ICI 182,780, an antagonist of the estrogen receptor, failed to block the inhibitory effect of estradiol on XDH/XO. In conclusion, 17α- and 17β-estradiol modulate the hypoxia-induced regulation of XDH/XO activity at a posttranscriptional level by a receptor-independent mechanism.

Original languageEnglish (US)
Pages (from-to)705-711
Number of pages7
JournalAntioxidants and Redox Signaling
Issue number6
StatePublished - Dec 2003

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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