DNA damage and lethal effects of hydrogen peroxide and menadione in Chinese hamster cells: distinct mechanisms are involved.
Menadione (Md)-resistant variants of V79 Chinese hamster cells were derived by culturing cells in progressively higher concentrations of this drug. Along with Md resistance these cells acquired cross-resistance to H2O2, which was retained when cells were cultured back in the absence of Md for 18 cell passages. This indicates that some stable alteration is responsible for the modification and may suggest that the toxicity of Md is mediated by oxygen activation. In agreement with the latter a 2.8-fold increase in catalase activity and a 1.5-fold increase in glutathione content were observed in Md-resistant cells as compared to parental cells, whereas superoxide dismutase and glutathione peroxidase remained unaltered. The use of inhibitors of Fenton reaction, inhibitors of enzymatic and nonenzymatic lipid peroxidation and OH radical scavengers, indicated that both DNA damage and cytotoxic effects of H2O2 and Md are mediated by OH radical, without intervention of lipid peroxides. However whereas the catalysis by iron was required for toxicity of extracellular H2O2, it was not involved in Md-induced toxicity. Possible explanations for this difference have been considered, one of them assuming that an excess of the semiquinone form of Md in the cell might replace iron II as a H2O2 reductant, producing OH radical by an organic Fenton reaction.
Martins
E A
EA
Department of Biochemistry, University of São Paulo, Brazil.
Meneghini
R
R
D000818:Animals; D002374:Catalase / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004249:DNA Damage; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung; D010100:Oxygen / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology*
D016166:Free Radical Scavengers; D005609:Free Radicals; D006878:Hydroxides; D014812:Vitamin K; D017665:Hydroxyl Radical; D006861:Hydrogen Peroxide; D002374:Catalase; D005978:Glutathione; D010100:Oxygen