Mechanisms of mutagenicity and toxicity of sodium selenite (Na2SeO3) in Salmonella typhimurium.
The mechanisms of selenite toxicity and mutagenicity in S. typhimurium have been characterized. In contrast to previous reports, selenite toxicity was shown not to involve nonspecific incorporation into protein via the sulfur metabolic pathways. Selenite toxicity was, however, shown to involve its ability to act as an oxidizing agent, primarily through reactions with sulfhydryls. Strains which lack glutathione (GSH) are more sensitive to killing by sulfhydryl reagents. The selenite sensitivity of such a mutant was a biphasic phenomenon. The mutant was much more sensitive than a strain which contained GSH at lower selenite concentrations whereas, at higher concentrations, the mutant was much more resistant to selenite. The mechanism of selenite toxicity at lower concentrations in this mutant thus appeared to involve damage to intracellular sulfhydryls. The sensitization to higher doses of selenite by GSH could be explained by the generation of toxic oxygen species. The in vitro reactions of selenite with both cysteine and GSH readily produced H2O2 and O2-. A S. typhimurium strain which overproduces superoxide dismutase (SOD) and catalase was more resistant to high concentrations of selenite, but not killing by the lower doses. Pretreatment of cells with a nonlethal dose of selenite induced the synthesis of proteins which protected the cells from killing by H2O2 or high doses of selenite. Selenite was also a mutagen in the tester strain TA104, in which a number of other oxidizing agents have also been found to be mutagens. These results were consistent with a model in which the reactions of selenite and intracellular thiols with concomitant production of active oxygen species are the primary causal agents of selenite mutagenicity and toxicity in S. typhimurium.
Kramer
G F
GF
Department of Biochemistry, University of California, Berkeley 94720.
Ames
B N
BN
D003545:Cysteine / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics; D005609:Free Radicals; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020887:Selenious Acid; D012643:Selenium / Q000494:pharmacology / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D005609:Free Radicals; D013438:Sulfhydryl Compounds; D013481:Superoxides; D013455:Sulfur; D006861:Hydrogen Peroxide; D020887:Selenious Acid; D005978:Glutathione; D012643:Selenium; D003545:Cysteine