Studies of selenium and arsenic mutual protection in human HepG2 cells.

Hundreds of millions of people worldwide are exposed to unacceptable levels of carcinogenic inorganic arsenic. Animal models have shown that selenium and arsenic are mutually protective through the formation and elimination of the seleno-bis(S-glutathionyl) arsinium ion [(GS)2AsSe]-. Consistent with this, human selenium deficiency in arsenic-endemic regions is associated with arsenic-induced disease, leading to the initiation of human selenium supplementation trials. In contrast to the protective effect observed in vivo, in vitro studies have suggested that selenite increases arsenite cellular retention and toxicity. This difference might be explained by the rapid conversion of selenite to selenide in vivo. In the current study, selenite did not protect the human hepatoma (HepG2) cell line against the toxicity of arsenite at equimolar concentrations, however selenide increased the IC50 by 2.3-fold. Cytotoxicity assays of arsenite + selenite and arsenite + selenide at different molar ratios revealed higher overall mutual antagonism of arsenite + selenide toxicity than arsenite + selenite. Despite this protective effect, in comparison to 75Se-selenite, HepG2 cells in suspension were at least 3-fold more efficient at accumulating selenium from reduced 75Se-selenide, and its accumulation was further increased by arsenite. X-ray fluorescence imaging of HepG2 cells also showed that arsenic accumulation, in the presence of selenide, was higher than in the presence of selenite. These results are consistent with a greater intracellular availability of selenide relative to selenite for protection against arsenite, and the formation and retention of a less toxic product, possibly [(GS)2AsSe]-.

Disruption of selenium transport and function is a major contributor to mercury toxicity in zebrafish larvae.

Mercury is one of the most toxic elements threatening the biosphere, with levels steadily rising due to both natural and human activities. Selenium is an essential micronutrient, required for normal development and functioning of many organisms. While selenium is known to counteract mercury's toxicity under some conditions, to date information about the mercury-selenium relationship is fragmented and often controversial. As part of a systematic study of mercury and selenium interactions, zebrafish (Danio rerio) larvae (a model verterbrate) were exposed to methylmercury chloride or mercuric chloride. The influence of pre- and post-treatment of selenomethionine on the level and distribution of mercury and selenium in the brain and eye sections, as well as on toxicity, were examined. Selenomethionine treatment decreased the amount of maternally transfered mercury in the larval brain. Selenomethionine treatment prior to exposure to mercuric chloride increased both mercury and selenium levels in the brain but decreased their toxic effects. Conversely, methylmercury levels were not changed as a result of selenium pre-treatment, while toxicity was increased. Strikingly, both forms of mercury severely disrupted selenium metabolism, not only by depleting selenium levels due to formation of Hg-Se complexes, but also by blocking selenium transport into and out of tissues, suggesting that restoring normal selenium levels by treating the organism with selenium after mercury exposure may not be possible. Disruption of selenium metabolism by mercury may lead to disruption in function of selenoproteins. Indeed, the production of thyroid hormones by selenoprotein deiodinases was found to be severely impaired as a result of mercury exposure, with selenomethionine not always being a suitable source of selenium to restore thyroid hormone levels.