alpha-Ketoacids scavenge H2O2 in vitro and in vivo and reduce menadione-induced DNA injury and cytotoxicity.
We demonstrate that alpha-ketoacids reduce and, in some instances, abrogate menadione-induced DNA damage and cytotoxicity in the human breast cancer cell line, MCF7. We confirm that alpha-ketoacids quench the copious amounts of H2O2 generated by menadione while these alpha-ketoacids undergo nonenzymatic oxidative decarboxylation; our data thus support enhanced H2O2 production as an important pathway for menadione-induced DNA damage and cytotoxicity. We also demonstrate that alpha-ketoacids scavenge H2O2 generated by mitochondria and microsomes when these organelles are exposed to menadione; additionally, alpha-ketoacids protect oxidant-vulnerable enzymes against functional impairment induced by H2O2. Finally, we provide the first in vivo demonstration that acute elevations in concentrations of alpha-ketoacids in rat tissues and urine scavenge H2O2. We conclude that enhanced H2O2 production is a major pathway for menadione-induced DNA damage and cytotoxicity and that the diverse alpha-ketoacids present within the cell must be considered, along with glutathione peroxidase and catalase, as part of the intracellular antioxidant defense mechanisms that regulate the ambient levels of H2O2.
Nath
K A
KA
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.
Ngo
E O
EO
Hebbel
R P
RP
Croatt
A J
AJ
Zhou
B
B
Nutter
L M
LM
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage; D003653:Decarboxylation; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000652:urine; D007651:Keto Acids / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018374:LLC-PK1 Cells / Q000187:drug effects; D010084:Oxidation-Reduction; D013347:Subcellular Fractions / Q000378:metabolism; D013552:Swine; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000494:pharmacology*
D016166:Free Radical Scavengers; D007651:Keto Acids; D014812:Vitamin K; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase