DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite.
Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide. Although its reactivity and decomposition are very much dependent on the constituents of the cellular environment, peroxynitrite is considered a potent oxidant that reacts with proteins, lipids, and DNA. Inasmuch as peroxynitrite is formed in many pathophysiological conditions that are associated with NO and/or superoxide overproduction, the investigation of the cytotoxic pathways triggered by peroxynitrite is of major importance. Here we review the evidence that peroxynitrite is a potent initiator of DNA strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly ADP ribosyl synthetase (PARS). We present an overview of experimental data that demonstrate or suggest that the peroxynitrite-PARS pathway, by leading to cell necrosis or apoptosis, contributes to cellular injury in a number of pathophysiological conditions including shock and inflammation, pancreatic islet cell destruction, and diabetes, stroke, and neurodegenerative disorders, as well as the toxic effects of various environmental oxidants or cytotoxic drugs.
Children's Hospital Medical Center, Division of Critical Care, Cineinnati, Ohio 45229, USA.
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Szabó
D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D003920:Diabetes Mellitus / Q000209:etiology; D004789:Enzyme Activation; D006801:Humans; D009566:Nitrates / Q000494:pharmacology* / Q000633:toxicity; D009569:Nitric Oxide / Q000633:toxicity; D016877:Oxidants / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D009569:Nitric Oxide; D011065:Poly(ADP-ribose) Polymerases