Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation

László Virág, Csaba Szabó

    Research output: Contribution to journalArticlepeer-review

    32 Scopus citations


    1. Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS). The cytotoxic PARS pathway initiated by DNA strand breaks and excessive PARS activation has been shown to deplete cellular energy pools, leading to cell necrosis. Here we have investigated the effect of tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) a heavy metal chelator on peroxynitrite-induced cytotoxicity. 2. TPEN (10 μM) abolished cell death induced by authentic peroxynitrite (25 μM) and the peroxynitrite generating agent 3-morpholinosidnonimine (SIN-1, 250 μM). Preincubation of TPEN with equimolar Zn2+ but not Ca2+ or Mg2+ blocked the cytoprotective effect of the chelator. 3. TPEN (10 μM) markedly reduced the peroxynitrite-induced decrease of mitochondrial transmembrane potential, secondary superoxide production and mitochondrial membrane damage, indicating that it acts proximal to mitochondrial alterations. 4. Although TPEN (1-300 μM) did not scavenge peroxynitrite, it inhibited PARS activation in a dose-dependent manner. 5. The cytoprotective effect of TPEN is only partly mediated via PARS inhibition, as the chelator also protected PARS-deficient thymocytes from peroxynitrite-induced death. 6. While being cytoprotective against peroxynitrite-induced necrotic death, TPEN (10 μM), similar to other agents that inhibit PARS, enhanced apoptosis (at 5-6 h after exposure), as characterized by phosphatydilserine exposure, caspase activation and DNA fragmentation. 7. In conclusion, the current data demonstrate that TPEN, most likely by zinc chelation, exerts protective effects against peroxynitrite-induced necrosis. Its effects are, in part, mediated by inhibition of PARS.

    Original languageEnglish (US)
    Pages (from-to)769-777
    Number of pages9
    JournalBritish Journal of Pharmacology
    Issue number3
    StatePublished - 1999


    • Cytotoxicity
    • Peroxynitrite
    • Poly(ADP-ribose) synthetase
    • TPEN
    • Zinc

    ASJC Scopus subject areas

    • Pharmacology


    Dive into the research topics of 'Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation'. Together they form a unique fingerprint.

    Cite this