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

摘要: Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation nuclear enzyme poly(ADP-ribose) synthetase (PARS). The cytotoxic PARS pathway initiated DNA strand breaks excessive has been shown to deplete cellular energy pools, leading cell necrosis. Here we have investigated effect tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) heavy metal chelator on peroxynitrite-induced cytotoxicity. TPEN (10 μM) abolished death induced authentic peroxynitrite (25 μM) generating agent 3-morpholinosidnonimine (SIN-1, 250 μM). Preincubation TPEN with equimolar Zn2+ but not Ca2+ or Mg2+ blocked cytoprotective chelator. TPEN markedly reduced decrease mitochondrial transmembrane potential, secondary production membrane damage, indicating that it acts proximal alterations. Although (1–300 μM) did scavenge peroxynitrite, inhibited dose-dependent manner. The is only partly mediated inhibition, as also protected PARS-deficient thymocytes from death. While being against necrotic death, (10 μM), similar other agents inhibit PARS, enhanced apoptosis (at 5–6 h after exposure), characterized phosphatydilserine exposure, caspase fragmentation. In conclusion, current data demonstrate TPEN, most likely zinc chelation, exerts protective effects Its are, inhibition PARS. British Journal Pharmacology (1999) 126, 769–777; doi:10.1038/sj.bjp.0702332