We demonstrate that α-ketoacids reduce and, in some instances, abrogate menadione-induced DNA damage and cytotoxicity in the human breast cancer cell line, MCF7. We confirm that α-ketoacids quench the copious amounts of H2O2 generated by menadione while these α-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 α-ketoacids scavenge H2O2 generated by mitochondria and microsomes when these organelles are exposed to menadione; additionally, α-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 α-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 α-ketoacids present within the cell must he considered, along with glutathione peroxidase and catalase, as part of the intracellular antioxidant defense mechanisms that regulate the ambient levels of H2O2.
ASJC Scopus subject areas
- Cell Biology