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Selenium (Se) is an essential trace element with a narrow margin between beneficial and toxic effects. As a promising chemopreventive agent, its use requires consumption over the long term, so the toxicity of Se is always a crucial concern. Based on clinical findings and recent studies in selenoprotein gene-modified mice, it is likely that the antioxidant function of one or more selenoproteins is responsible for the chemopreventive effect of Se. Furthermore, upregulation of phase 2 enzymes by Se has been implicated as a possible chemopreventive mechanism at supranutritional dietary levels. Se-methylselenocysteine (SeMSC), a naturally occurring organic Se product, is considered as one of the most effective chemopreventive selenocompounds. The present study revealed that, as compared with SeMSC, elemental Se at nano size (Nano-Se) possessed equal efficacy in increasing the activities of glutathione peroxidase, thioredoxin reductase, and glutathione S-transferase, but had much lower toxicity as indicated by median lethal dose, acute liver injury, survival rate, and short-term toxicity. Our results suggest that Nano-Se can serve as a potential chemopreventive agent with reduced risk of Se toxicity.

It has been shown that 36 nm Nano-Se has lower toxicity than selenite or selenomethionine, but these forms of selenium (Se) all possess similar ability to increase selenoenzyme levels. The size of nanoparticles plays an important role in their biological activity: as expected, 5-200 nm Nano-Se can directly scavenge free radicals in vitro in a size-dependent fashion. However, in Se-deficient cells and Se-deficient mice, the size effect of Nano-Se on increasing selenoenzymes and liver Se disappears unexpectedly. We hypothesize that under conditions of Se deficiency, the avidity of Se uptake mechanisms may be increased to maintain the biosynthesis of selenoenzymes, which are fundamental for redox homeostasis. This increased avidity may override the potential advantage of small size Nano-Se seen under Se-replete conditions, thereby eliminating the size effect. Once selenoenzymes have been saturated, Se uptake mechanisms may downregulate; accordingly, the size effect of Nano-Se can then reappear. To test this hypothesis, Se-deficient mice were administered either 36 or 90 nm Nano-Se at supranutritional doses, in both a short-term model and a single-dose model. Under these conditions, Nano-Se showed a size effect on Se accumulation and glutathione S-transferase (GST) activity. A size effect of Nano-Se was found in 15 out of 18 total comparisons between sizes at the same dose and time in the two models. Furthermore, the magnitude of the size effect was more prominent on Se accumulation than on GST activity. GST is strictly regulated by transcriptional and translational mechanisms, so its increase in activity normally does not exceed 3-fold. In contrast, the homeostasis of Se accumulation is not as tightly controlled. In the present experiments, GST activity had reached or was approaching saturation, but liver Se was far below saturation. Therefore, our results strongly suggest that the saturation profile of the tested biomarker has an impact on the size effect of Nano-Se. Since both GST and small molecular weight selenocompounds accumulated in vivo are important intermediates for chemoprevention by Se, our results also suggest that Nano-Se should be most effective as a chemopreventive agent at smaller particle size.

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