Effect of pyruvate on oxidant injury to isolated and cellular DNA.
Drawing upon the capacity of pyruvate to detoxify H2O2, we demonstrate that pyruvate (i) protects against H2O2-dependent, hydroxyl radical-mediated degradation of isolated DNA; (ii) reduces the amount of 8-hydroxy-2-deoxyguanosine detected following oxidative injury to isolated DNA and (iii) diminishes the amounts of detectable hydroxyl radical generated by a H2O2-dependent system. Compared to mannitol, pyruvate protects weakly against oxidative degradation of DNA induced by a H2O2-independent, hydroxyl radical-generating system. The protective effects of pyruvate against H2O2-instigated DNA damage were also evinced in cells in culture exposed to H2O2. In contrast to its protective effects against H2O2-dependent injury to DNA, pyruvate failed to offer convincing protection to another intracellular, H2O2-vulnerable target, glyceraldehyde-3-phosphate dehydrogenase. The protection conferred by pyruvate to intracellular H2O2-vulnerable targets is thus influenced by the nature of the target exposed to H2O2. Pyruvate was markedly protective in a model of cytotoxicity induced by the concomitant depletion of cellular glutathione and inhibition of catalase activity; pyruvate can thus function as an intracellular antioxidant and in this latter model, no evidence of DNA damage was observed. Pyruvate, in contrast to catalase, is a potent protector against cytotoxicity induced by organic peroxides, a finding that cannot be explained by the scavenging of organic peroxides, differences in glutathione content or attenuation in oxidative injury to DNA. We conclude that while DNA damage is a key pathogenetic event in oxidative stress induced by H2O2, such nuclear changes may not universally subserve a critical role in models of H2O2-dependent cell death. We also conclude that the antioxidant capabilities of pyruvate extend beyond scavenging of H2O2 to include potent protection against cytotoxicity induced by organic peroxides.
Nath
K A
KA
Department of Medicine, University of Minnesota School of Medicine, Minneapolis.
Enright
H
H
Nutter
L
L
Fischereder
M
M
Zou
J N
JN
Hebbel
R P
RP
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D005978:Glutathione / Q000172:deficiency; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D010545:Peroxides / Q000494:pharmacology; D011773:Pyruvates / Q000494:pharmacology*; D019289:Pyruvic Acid
D010545:Peroxides; D011773:Pyruvates; D017665:Hydroxyl Radical; D019289:Pyruvic Acid; D004247:DNA; D006861:Hydrogen Peroxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005978:Glutathione