Multidrug and toxin extrusion proteins mediate cellular transport of cadmium

Cadmium (Cd) is an environmentally prevalent toxicant posing increasing risk to human health worldwide. As compared to the extensive research in Cd tissue accumulation, little was known about the elimination of Cd, particularly its toxic form, Cd ion (Cd2+). In this study, we aimed to examine whether Cd2+ is a substrate of multi drug and toxin extrusion proteins (MATEs) that are important in renal xenobiotic elimination. HEK-293 cells overexpressing the human MATE1 (HEK-hMATE1), human MATE2-K (HEK-hMATE2-K) and mouse Matel (HEK-mMate1) were used to study the cellular transport and toxicity of Cd2+. The cells overexpressing MATES showed a 2-4 fold increase of Cd2+ uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (K-m) of 130 +/- 15.8 mu M for HEK-hMATE1; 139 +/- 213 mu M for HEK-hMATE2-K; and 88.7 +/- 13.5 mu M for HEK-mMate1, respectively. Cd2+ could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC50) of 97.5 +/- 6.0 mu M, 20.2 +/- 2.6 mu M, and 49.9 +/- 6.9 mu M in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd2+ out of the HEK-hMATE1 cells, thus resulting in a significant decrease of Cd2+ -induced cytotoxicity. The present study has provided the first evidence supporting that MATEs transport Cd2+ and may function as cellular elimination machinery in Cd intoxication. (C) 2016 Elsevier Inc. All rights reserved.