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.
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455.
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Croatt
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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