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// Joseph R. McDermott 1 , Xiangrong Geng 1 , Lan Jiang 1 , Marina Galvez-Peralta 2 , Fei Chen 3 , Daniel W. Nebert 2 , Zijuan Liu 1 1 Department of Biological Sciences, Oakland University, Rochester, MI 48309, USA 2 Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA 3 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA Correspondence to: Daniel W. Nebert, email: dan.nebert@uc.edu Zijuan Liu, email: liu2345@oakland.edu Keywords: selenite, zinc, micronutrient, ZIP8, membrane-bound transporter Received: December 26, 2015 Accepted: April 11, 2016 Published: May 6, 2016 ABSTRACT Selenite (HSeO 3 − ) is a monovalent anion of the essential trace element and micronutrient selenium (Se). In therapeutic concentrations, HSeO 3 − has been studied for treating certain cancers, serious inflammatory disorders, and septic shock. Little is known, however, about HSeO 3 − uptake into mammalian cells; until now, no mammalian HSeO 3 − uptake transporter has been identified. The ubiquitous mammalian ZIP8 divalent cation transporter (encoded by the SLC39A8 gene) is bicarbonate-dependent, moving endogenous substrates (Zn 2+ , Mn 2+ , Fe 2+ or Co 2+ ) and nonessential metals such as Cd 2+ into the cell. Herein we studied HSeO 3 − uptake in: human and mouse cell cultures, shRNA-knockdown experiments, Xenopus oocytes, wild-type mice and two transgenic mouse lines having genetically altered ZIP8 expression, and mouse erythrocytes ex vivo . In mammalian cell culture, excess Zn 2+ levels and/or ZIP8 over-expression can be associated with diminished viability in selenite-treated cells. Intraperitoneal HSeO 3 − causes the largest ZIP8-dependent increases in intracellular Se content in liver, followed by kidney, heart, lung and spleen. In every model system studied, HSeO 3 − uptake is tightly associated with ZIP8 protein levels and sufficient Zn 2+ and HCO 3 − concentrations, suggesting that the ZIP8-mediated electroneutral complex transported contains three ions: Zn 2+ /(HCO 3 − )(HSeO 3 − ). Transporters having three different ions in their transport complex are not without precedent. Although there might be other HSeO 3 − influx transporters as yet undiscovered, data herein suggest that mammalian ZIP8 plays a major role in HSeO 3 − uptake.