Mutagenicity of nitric oxide and its inhibition by antioxidants.
Nitric oxide (NO) is produced both by macrophages in vivo as a physiological response to infection and by a variety of cell types as an intercellular messenger. In addition, NO and nitrogen dioxide (NO2) are significant components of many combustion processes. The ubiquitous exposure of humans to nitrogen oxides (NOx), both endogenously and exogenously, may play a significant role in the carcinogenic process due to nitrosation of amines by NOx. We report here that exposure to low concentrations of NO, alone or in combination with NO2, results in significantly enhanced mutation in Salmonella typhimurium TA1535 using a modified Ames Salmonella reversion assay. The observed mutagenicity requires that the bacteria be actively dividing at the time of exposure to NO or NO2, suggesting that the nitrogen oxides, or their reaction products, function as direct-acting mutagens and that the induced lesion is easily repairable by non-dividing cells. Exposure to NO resulted in a time- and dose-dependent increase in the number of revertants approximately proportional to the square of the NO concentration from 0 to 20 ppm. NO was a more effective mutagen relative to NO2, however, the observed requirement for O2 suggests limited oxidation of NO (presumably to NO2) is necessary. Numerous lipid- and aqueous-phase inhibitors of nitrosation, as well as a number of other general antioxidants and free-radical trapping agents, were examined for their effectiveness in blocking the mutagenic effects of NO. The mutagenic activity of NO was most effectively inhibited by beta-carotene and tocopherols. BHT, dimethyl sulfoxide and mannitol also blocked the mutagenic effects of NOx but appeared less effective than beta-carotene or vitamin E, while ascorbate was ineffective as an inhibitor of mutation resulting from NO exposure.
University of Hawaii, Cancer Research Center of Hawaii, Honolulu 96813.
P L
PL
Arroyo
V
V
Hatch-Pigott
H F
HF
Mower
R V
RV
Cooney
D000975:Antioxidants / Q000494:pharmacology*; D002338:Carotenoids / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009585:Nitrogen Dioxide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009602:Nitrosamines / Q000032:analysis; D012486:Salmonella typhimurium / Q000187:drug effects; D014810:Vitamin E / Q000494:pharmacology; D019207:beta Carotene
D000975:Antioxidants; D009153:Mutagens; D009602:Nitrosamines; D019207:beta Carotene; D014810:Vitamin E; D009569:Nitric Oxide; D002338:Carotenoids; D009585:Nitrogen Dioxide; D004121:Dimethyl Sulfoxide