Animal studies suggesting that selenium was effective in the reduction of cancer incidence have been described in the literature for decades. These reports have indicated the efficiency of selenium in the protection of most organ and tissue types following exposure to a wide variety of carcinogens, including chemicals, viruses, and ionizing radiation. Recently, a clinical trial in the Southeastern United States has indicated low level dietary, supplementation with selenium could significantly reduce the incidence of colon, lung, and prostate cancer. We have shown that selenium was effective in reducing the frequency of radiation-induced mutations in CHO AA8 cells. In these experiments, the protective effect of selenium was associated with an approximately 5-fold increase in the activity of the anti-oxidant selenoprotein, glutathione peroxidase (SeGPx). It is hypothesized that the selenium-mediated protection against radiation-induced mutagenesis occurs by the stimulation of the anti-oxidant activity of SeGPx. The mechanism by which selenium protects against mutagenesis at the hypoxanthine guanine phosphoribosyl transferase (hprt) locus will be evaluated by increasing the glutathione peroxidase activity independent of selenium supplementation by transfection of a glutathione peroxidase expression construct into AA8 cells. In addition, the inhibition of radiation-induced DNA damage by selenium and glutathione peroxidase will be evaluated to further elucidate the mechanism(s) of protection. DNA damage will be measured using alkaline elution to assess single strand break formation and HPLC with electrochemical will be used to quantitate 8-hydroxy-2'-deoxyguanosine, a product of oxidative damage. The mechanism of post-transcriptional stimulation of SeGPx activity be selenium will be investigated by studying qualitative and quantitative changes in selenocysteine tRNAs, the central component of all selenoprotein biosynthesis. Finally, similar studies will be conducted in a mouse model system to evaluate whether our cell culture observations can be extended to whole animals. Collectively, these studies will determine the optimal conditions for the anti-mutagenic effects of selenium and will allow for the evaluation of the mechanism(s) of action.
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