Purines inhibit poly(ADP-ribose polymerase activation and modulate oxidant-induced cell death

L. Virag, C. Szabó

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

Purines such as adenosine, inosine, and hypoxanthine are known to have potent antiinflammatory effects. These effects generally are believed to be mediated by cell surface adenosine receptors. Here we provide evidence that purines protect against oxidant-induced cell injury by inhibiting the activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Upon binding to broken DNA, PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins such as histones and PARP itself. Overactivation of PARP depletes cellular NAD+ and ATP stores and causes necrotic cell death. We have identified some purines (hypoxanthine, inosine, and adenosine) as potential endogenous PARP inhibitors. We have found that purines (hypoxanthine > inosine > adenosine) dose-dependently inhibited PARP activation in peroxynitrite-treated macrophages and also inhibited the activity of the purified PARP enzyme. Consistently with their PARP inhibitory effects, the purines also protected interferon γ + endotoxin (IFN/LPS) -stimulated RAW macrophages from the inhibition of mitochondrial respiration and inhibited nitrite production from IFN/LPS-stimulated macrophages. We have selected hypoxanthine as the most potent cytoprotective agent and PARP inhibitor among the three purine compounds, and investigated the mechanism of its cytoprotective effect. We have found that hypoxanthine protects thymocytes from death induced by the cytotoxic oxidant peroxynitrite. In line with the PARP inhibitory effect of purines, hypoxanthine has prevented necrotic cell death while increasing caspase activity and DNA fragmentation. As previously shown with other PARP inhibitors, hypoxanthine acted proximal to mitochondrial alterations as hypoxanthine inhibited the peroxynitrite-induced mitochondrial depolarization and secondary superoxide production. Our data imply that purines may serve as endogenous PARP inhibitors. We propose that, by affecting PARP activation, purines may modulate the pattern of cell death during shock, inflammation, and reperfusion injury.

Original languageEnglish
Pages (from-to)99-107
Number of pages9
JournalFASEB Journal
Volume15
Issue number1
DOIs
Publication statusPublished - 2001

Fingerprint

NAD ADP-ribosyltransferase
Purines
Poly(ADP-ribose) Polymerases
Hypoxanthine
Cell death
purines
Oxidants
oxidants
cell death
Cell Death
hypoxanthine
Chemical activation
Inosine
Peroxynitrous Acid
Macrophages
adenosine
Adenosine
NAD
macrophages
Adenosine Diphosphate Ribose

Keywords

  • ADP-RT
  • Antioxidants
  • Free radicals
  • Knockout
  • Nitric oxide
  • Shock

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Purines inhibit poly(ADP-ribose polymerase activation and modulate oxidant-induced cell death. / Virag, L.; Szabó, C.

In: FASEB Journal, Vol. 15, No. 1, 2001, p. 99-107.

Research output: Contribution to journalArticle

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