Table 1

Pathophysiologically relevant sources of oxidant and free radical species capable of PARP activation

Reactive Oxygen or Nitrogen SpeciesCellular SourcesDiffusible?Relationship to PARP Activation
Superoxide anionMitochondrial respiratory chain, activated neutrophils, macrophages, xanthine oxidase, lipid peroxidation, catechol auto-oxidation, redox cyclingYesDoes not induce DNA single strand breakage of PARP activation; although not a particularly potent oxidant, it can be cytotoxic via a number of PARP-independent mechanisms.
Hydrogen peroxideXanthine oxidase, mitochondrial respiratory chain, catechol auto-oxidation, redox cyclingYesPotent trigger of DNA single strand breakage and PARP activation via the generation of hydroxyl radical in the vicinity of DNA; potent oxidizing agent; can also be cytotoxic via a number of PARP-independent mechanisms.
Hydroxyl radicalFrom hydrogen peroxide, via the classic Fenton reaction. Monoamine oxidase in response to ionizing radiation, catechol auto-oxidation, redox cyclingNoPotent trigger of DNA single strand breakage and PARP activation; can also be cytotoxic via a number of PARP-independent mechanisms. The decomposition of peroxynitrite yields a hydroxyl radical-like intermediate, which, however, does not appear to be “free” hydroxyl radical.
Hypochlorous acidActivated granulocytesYesDoes not induce DNA single strand breakage or PARP activation; can be cytotoxic via a number of PARP-independent mechanisms. At high concentrations, it is able to directly inactivate PARP.
Nitric oxideNitric-oxide synthases, acidification of nitrite, non-enzymatic pathwaysYesDoes not induce DNA single strand breakage or PARP activation, unless it combines with superoxide to produce peroxynitrite. Although not a particularly potent oxidant, can be cytotoxic via a number of PARP-independent mechanisms. It can also exert marked antioxidant and cytoprotective actions.
PeroxynitriteReaction of nitric oxide and superoxide. Nitric-oxide synthases can produce peroxynitrite under conditions of low cellular l-arginine levelsYesPotent trigger of DNA single strand breakage through a hydroxyl radical-like intermediate. Potent trigger of PARP-activation; can also be cytotoxic via a number of PARP-independent mechanisms.
Nitroxonium anionNitric oxideYesTrigger of DNA single and double strand breakage; triggers PARP activation and associated cell death; can also be cytotoxic via a number of PARP-independent mechanisms.