Abstract
Nitric oxide (NO) has been reported to impart, alone or in combination with reactive oxygen species (ROS), the cytotoxicity and putative genotoxicity associated with the immunological response. The present study examined the change in the mutagenic activity profile of the NO-donor spermine NONOate (SperNO) as a result of introduction of hydrogen peroxide (H(2)O(2)) to the Ames assay. The aim was to determine whether the assay could detect H(2)O(2)-induced co- or anti-mutagenic effects on NO-induced mutagenesis, and the Salmonella typhimurium base-pair substitution tester strain TA1535 provided an appropriate tool. While TA1535 was shown by the authors and others to be strongly sensitive to NO-induced mutagenesis, it has also been shown to be insensitive to H(2)O(2)-induced mutagenicity [1,2]. When H(2)O(2) (0.25-4.0 micromol/pl) was added directly to cells treated with SperNO (0.01-1.0 micromol/pl), co-mutagenicity was not detected, but a drop in reversion count and detectable toxicity was observed, especially at doses > 0.1 micromol/pl. When glucose/glucose oxidase (GOX) or reduced glutathione (GSH) were used as H(2)O(2)-generation systems the results varied. Reversion induced by SperNO (1 micromol/pl) was moderately enhanced by GOX (10-20 mUnits/pl), but the increase albeit reproducible did not reach a doubling (co-mutagenicity). GOX (40 micromol/pl) induced a reduction in reversion count, but no visible toxicity. On the other hand, GSH (20- 80 micromol/pl) gave a strong co-mutagenic effect. Co-mutagenicity was highest (> 5x) at 80 micromol/pl GSH and 0.1 micromol/pl SperNO. Based on these findings, it could be concluded that a) H(2)O(2), when steadily generated in the cell, has a modulatory effect on NO-mutagenicity, and such a conclusion is not inconsistent with the wide range of responses reported for the two chemicals, and/or b) the observed co-mutagenic effects of GSH may not be attributable solely to H(2)O(2) generation.
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