Toxicity, radiation sensitivity modification, and metabolic effects of dehydroascorbate and ascorbate in mammalian cells.
Dehydroascorbate, an electron affinic metabolite of vitamin C, sensitized Ehrlich ascites tumor cells, in vivo, to radiation and was selectively toxic to V79 Chinese hamster lung cells under hypoxic conditions (without radiation). The radiosensitization may involve both the electron affinic nature of dehydroascorbate as well as its ability to oxidize the intracellular NAD(P)H and non-protein sulfhydryl. Dehydroascorbate's oxidation of NAD(P)H required higher concentrations than other sulfhydryl oxidants such as N-ethylmaleimide and diamide. The oxidation of NAD(P)H by dehydroascorbate could be reversed by glucose. Hypoxic cell radiosensitization of V79 cells in tissue culture by dehydroascorbate could not be easily demonstrated because of the rapid breakdown and appreciable cytotoxicity of the drug at high concentration. The cytotoxicity was found to occur with both high and low densities of V79 cells. With low cell densities small amounts of oxygen did not reduce the cytotoxicity of dehydroascorbate, but virtually eliminated the cytotoxicity of nitroaromatic electron affinic compounds (metronidazole and Ro-07-0582). The cytotoxicity to dense cell suspensions was found to depend upon the type of buffer included in the reaction medium. The maximum cytotoxicity was obtained in buffer free saline. The reduced form of dehydroascorbate, vitamin C, was found to be toxic only under aerobic conditions. The aerobic cytotoxicity could be prevented by the addition of catalase to the growth medium or by an increase in cell density, suggesting it was caused entirely by the production of H2O2 from the oxidation of vitamin C.
D000332:Aerobiosis; D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D006224:Cricetinae; D003683:Dehydroascorbic Acid / Q000494:pharmacology*; D003958:Diamide / Q000494:pharmacology; D005033:Ethylmaleimide / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009249:NADP / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000633:toxicity; D013438:Sulfhydryl Compounds / Q000378:metabolism
D011838:Radiation-Sensitizing Agents; D013438:Sulfhydryl Compounds; D003958:Diamide; D009249:NADP; D005033:Ethylmaleimide; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid