THE INHIBITION OF RADIATION-INDUCED MUTAGENESIS BY THE COMBINED EFFECTS OF SELENIUM AND THE AMINOTHIOL WR-1065

In order to evaluate the anti-mutagenic effects of the potential chemo protective compounds selenium and (S)-2-(3-aminopropylamino)ethylphosp horothioic acid (WR-1065), CHO AA8 cells were exposed to both compound s either individually or in combination prior to irradiation. Mutation frequency following exposure to 8 Gy was evaluated by quantitation of the mutations detected at the hprt locus of these cells. Protection a gainst radiation-induced mutation was observed for both 30 nM sodium s elenite or 4 mM WR-1065. In addition, the protection against mutation induction provided by the combination of these agents appeared additiv e. In contrast, sodium selenite did not provide protection against rad iation toxicity when provided either alone or in conjunction with WR-1 065. In order to evaluate the possible mechanisms of the anti-mutageni c effects observed in these cells, glutathione peroxidase (GPx) activi ty was evaluated following exposure to the chemopreventative compounds . The addition of sodium selenite to the culture media resulted in a 5 -fold increase in GPx activity, which was unaltered by the presence of the WR-1065. Northern analysis of RNA derived from these cells indica ted that selenium supplementation resulted in a marginal increase in t he mRNA for the cytosolic GPx (GSHPx-1) which was insufficient to acco unt for the stimulation of GPx activity observed in cellular extracts. These results suggest that selenium and WR-1065 offer protection via independent mechanisms and that GPx stimulation remains a possible mec hanism of the anti-mutagenic effect of selenium.