Peroxynitrite-induced cytotoxicity

Mechanism and opportunities for intervention

László Virág, Éva Szabó, Pál Gergely, Csaba Szabo

Research output: Contribution to journalArticle

355 Citations (Scopus)

Abstract

Peroxynitrite is formed in biological systems when superoxide and nitric oxide are produced at near equimolar ratio. Although not a free radical by chemical nature (as it has no unpaired electron), peroxynitrite is a powerful oxidant exhibiting a wide array of tissue damaging effects ranging from lipid peroxidation, inactivation of enzymes and ion channels via protein oxidation and nitration to inhibition of mitochondrial respiration. Low concentrations of peroxynitrite trigger apoptotic death, whereas higher concentrations induce necrosis with cellular energetics (ATP and NAD) serving as switch between the two modes of cell death. Peroxynitrite also damages DNA and thus triggers the activation of DNA repair systems. A DNA nick sensor enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) also becomes activated upon sensing DNA breakage. Activated PARP-1 cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite-induced overactivation of PARP consumes NAD+ and consequently ATP culminating in cell dysfunction, apoptosis or necrosis. This cellular suicide mechanism has been implicated among others in the pathomechanism of stroke, myocardial ischemia, diabetes and diabetes-associated cardiovascular dysfunction. Here, we review the cytotoxic effects (apoptosis and necrosis) of peroxynitrite focusing on the role of accelerated ADP-ribose turnover. Regulatory mechanisms of peroxynitrite-induced cytotoxicity such as antioxidant status, calcium signalling, NFκB activation, protein phosphorylation, cellular adaptation are also discussed.

Original languageEnglish (US)
Pages (from-to)113-124
Number of pages12
JournalToxicology Letters
Volume140-141
DOIs
StatePublished - Apr 11 2003
Externally publishedYes

Fingerprint

Peroxynitrous Acid
Cytotoxicity
NAD
Adenosine Diphosphate Ribose
Necrosis
Poly(ADP-ribose) Polymerases
DNA
Medical problems
Enzyme sensors
Adenosine Triphosphate
Chemical activation
Apoptosis
Nitration
Single-Stranded DNA Breaks
Phosphorylation
Calcium Signaling
Cell death
Biological systems
Enzymes
Nuclear Proteins

Keywords

  • Apoptosis
  • Cytotoxicity
  • Necrosis
  • Peroxynitrite
  • Poly(ADP-ribose) glycohydrolase
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Toxicology

Cite this

Peroxynitrite-induced cytotoxicity : Mechanism and opportunities for intervention. / Virág, László; Szabó, Éva; Gergely, Pál; Szabo, Csaba.

In: Toxicology Letters, Vol. 140-141, 11.04.2003, p. 113-124.

Research output: Contribution to journalArticle

Virág, László ; Szabó, Éva ; Gergely, Pál ; Szabo, Csaba. / Peroxynitrite-induced cytotoxicity : Mechanism and opportunities for intervention. In: Toxicology Letters. 2003 ; Vol. 140-141. pp. 113-124.
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