Sb(Ⅴ) has distinct cellular uptake route and cytotoxic mechanism from Sb(Ⅲ): Anion channel 2 and sulfhydryl binding

Antimony (Sb), a metalloid element with important industrial applications, exists as valence states of Sb(III) and Sb(V). Understanding on the Sb induced cytotoxicity, especially Sb(V), is still limited. In this study, human hepatoma (HepG2) and nephrocyte (HEK293T) cell lines were used to investigate the cytotoxicity, uptake and biotransformation of Sb. The mechanisms of cytotoxicity are different for Sb(III) and Sb(V). Sb(III) induces oxidative stress, while Sb(V) binds to sulfhydryl groups (SH) to cause cytotoxicity. Both HepG2 and HEK293T cells took up more Sb(III) than Sb(Ⅴ). We report for the first time that Sb(V) uptake through anion channel 2 (AE2), but Sb(III) uptake is through aquaglyceroporin-9 (AQP9). Higher cellular uptake and different uptake channels may contribute to the higher toxicity of Sb(III) than Sb(V). The reduction of Sb(Ⅴ) to Sb(III) in cells was revealed by HG-HPLC-AFS. Approximately 14.21 % of Sb(V) was reduced to Sb(III), but the oxidation of Sb(III) to Sb(V) was not found. Glutathione performed important role in the reduction of Sb(V). Our research elucidates the mechanisms of Sb cytotoxicity and uptake, which provides a theoretical basis to predict the health risks of Sb.