Human red blood cell uptake and sequestration of arsenite and selenite: Evidence of seleno-bis(S-glutathionyl) arsinium ion formation in human cells

Over 200 million people worldwide are exposed to the human carcinogen, arsenic, in contaminated drinking water. In laboratory animals, arsenic and the essential trace element, selenium, can undergo mutual detoxification through the formation of the seleno-bis(S-glutathionyl) arsinium ion [(GS)₂AsSe]⁻, which undergoes biliary and fecal elimination. [(GS)₂AsSe]⁻, formed in animal red blood cells (RBCs), sequesters arsenic and selenium, and slows the distribution of both compounds to peripheral tissues susceptible to toxic effects. In human RBCs, the influence of arsenic on selenium accumulation, and vice versa, is largely unknown. The study aims were to characterize arsenite (As^III) and selenite (Se^IV) uptake by human RBCs, to determine if Se^IV and As^III increase the respective accumulation of the other in human RBCs, and ultimately to determine if this occurs through the formation and sequestration of [(GS)₂AsSe]⁻. ⁷⁵Se^IV accumulation was temperature and Cl⁻-dependent, inhibited by 4,4′-diisothiocyanatodihydrostilbene-2,2′-disulfonic acid (H₂DIDS) (IC₅₀ 1 ± 0.2 µM), and approached saturation at 30 µM, suggesting uptake is mediated by the erythrocyte anion-exchanger 1 (AE1 or Band 3, gene SLC4A1). HEK293 cells overexpressing AE1 showed concentration-dependent ⁷⁵Se^IV uptake. ⁷³As^III uptake by human RBCs was temperature-dependent, partly reduced by aquaglyceroporin 3 inhibitors, and not saturated. As^III increased ⁷⁵Se^IV accumulation (in the presence of albumin) and Se^IV increased ⁷³As^III accumulation in human RBCs. Near-edge X-ray absorption spectroscopy revealed the formation of [(GS)₂AsSe]⁻ in human RBCs exposed to both As^III and Se^IV. The sequestration of [(GS)₂AsSe]⁻ in human RBCs potentially slows arsenic distribution to susceptible tissues and could reduce arsenic-induced disease.