Nitroxide SOD-mimics: modes of action.
Low molecular weight superoxide dismutase mimics have been shown to afford protection from oxidative damage. Such SOD-mimics can readily permeate cell membrane achieving sufficiently high levels both inside and outside the cell to effectively detoxify intracellular O2-.. Preliminary findings also indicated that metal-based and metal-free SOD-mimics can protect hypoxic cells from H2O2-induced damage. The present study explored the possibility that SOD-mimics such as desferrioxamine-Mn(III) chelate [DF-Mn] or cyclic nitroxide stable free radicals could protect from O2-.-independent damage. Killing of monolayered V79 Chinese hamster cells was induced by H2O2 or by t-butyl hydroperoxide (t-BHP) and assayed clonogenically. Neither catalase nor native SOD protected the cells from t-BHP. In contrast, both DF-Mn and cyclic nitroxides protected suggesting cytotoxic processes independent of O2-. or of O2-.-derived active species. The inhibition of the damage by both metal-free and metal-based SOD mimics is attributable to either SOD-mimic reacting with reduced transition metal to block the Fenton reaction and/or intercepting and detoxifying intracellular organic free radicals.
Samuni
A
A
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Mitchell
J B
JB
DeGraff
W
W
Krishna
C M
CM
Samuni
U
U
Russo
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology* / Q000031:analogs & derivatives; D005347:Fibroblasts / Q000187:drug effects; D016166:Free Radical Scavengers; D005609:Free Radicals; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008168:Lung; D008956:Models, Chemical; D009942:Organometallic Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D010545:Peroxides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D020122:tert-Butylhydroperoxide
D000975:Antioxidants; D003497:Cyclic N-Oxides; D003574:Cytochrome c Group; D016166:Free Radical Scavengers; D005609:Free Radicals; D009942:Organometallic Compounds; D010545:Peroxides; D013113:Spin Labels; D013481:Superoxides; C068338:manganese desferioxamine; D020122:tert-Butylhydroperoxide; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D003676:Deferoxamine; C001803:tempol