N-hydroxyguanidine compound 1-(3,4-dimethoxy-2-chlorobenzylideneamino)- 3-hydroxyguanidine inhibits the xanthine oxidase mediated generation of superoxide radical

Maija Dambrova, Larisa Baumane, Anne Kiuru, Ivars Kalvinsh, Jarl E.S. Wikberg

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

We here show that the novel N-hydroxyguanidine derivative PR5 (1-(3,4- dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine) is acting as an alternative electron acceptor in xanthine oxidase catalyzed oxidation of xanthine. The reduction product is the corresponding guanidine derivative 1- (3,4-dimethoxy-2-chlorobenzylideneamino)guanidine (PR9). The reaction occurs under both anaerobic and aerobic conditions. Moreover, EPR measurements show that the action of PR5 is associated with the inhibition of superoxide radical formation seen under aerobic conditions. PR5 also supports xanthine oxidase catalyzed anaerobic oxidation of NADH. Kinetic studies indicate that increasing xanthine concentration significantly increases the apparent K(m) of PR5, but it remains unaltered by changing NADH concentration. Moreover, the molybdenum center inhibitor allopurinol inhibits the PR5-sustained oxidation of xanthine and NADH equally well, whereas the flavin adenine dinucleotide site inhibitor diphenyliodonium (DPI) markedly inhibits only the PR5-sustained oxidation of NADH. We suggest that PR5 binds and becomes reduced at the molybdenum center of the xanthine oxidase. We also found that both PR5 and its reduction product PR9 can inhibit the oxygen-sustained xanthine oxidase reaction. The properties of PR5 suggest that it is a member of a novel class of compounds which we have termed xanthine oxidase electron acceptor-inhibitor drugs. The potential use of xanthine oxidase electron acceptor-inhibitors in the prevention of free radical mediated tissue damage in organ ischemia-reperfusion diseases is discussed. (C) 2000 Academic Press.

Original languageEnglish
Pages (from-to)101-108
Number of pages8
JournalArchives of Biochemistry and Biophysics
Volume377
Issue number1
DOIs
Publication statusPublished - 1 May 2000
Externally publishedYes

Keywords

  • Allopurinol
  • EPR
  • Inhibitor
  • N-hydroxyguanidine derivative
  • Superoxide
  • Xanthine oxidase

Field of Science

  • 1.4 Chemical sciences
  • 1.6 Biological sciences
  • 3.1 Basic medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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