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 chemoprotective compounds selenium and (S)-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-1065), CHO AA8 cells were exposed to both compounds 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 against radiation-induced mutation was observed for both 30 nM sodium selenite or 4 mM WR-1065. In addition, the protection against mutation induction provided by the combination of these agents appeared additive. In contrast, sodium selenite did not provide protection against radiation toxicity when provided either alone or in conjunction with WR-1065. In order to evaluate the possible mechanisms of the anti-mutagenic effects observed in these cells, glutathione peroxidase (GPx) activity 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 indicated that selenium supplementation resulted in a marginal increase in the mRNA for the cytosolic GPx (GSHPx-1) which was insufficient to account 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 mechanism of the anti-mutagenic effect of selenium.
Diamond
A M
AM
Department of Radiation and Cellular Oncology, University of Chicago, IL 60637, USA.
Dale
P
P
Murray
J L
JL
Grdina
D J
DJ
D000818:Animals; D015152:Blotting, Northern; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D005979:Glutathione Peroxidase / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008624:Mercaptoethylamines / Q000494:pharmacology*; D016296:Mutagenesis / Q000187:drug effects* / Q000528:radiation effects*; D009152:Mutagenicity Tests; D012333:RNA, Messenger / Q000032:analysis; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012643:Selenium / Q000494:pharmacology*
D008624:Mercaptoethylamines; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D005979:Glutathione Peroxidase; D007041:Hypoxanthine Phosphoribosyltransferase; D012643:Selenium