title: Multidrug and toxin extrusion proteins mediate cellular transport of cadmium.
abstract: 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 multidrug 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 Mate1 (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 (Km) of 130±15.8μM for HEK-hMATE1; 139±21.3μM for HEK-hMATE2-K; and 88.7±13.5μM 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±6.0μM, 20.2±2.6μM, and 49.9±6.9μM 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA.
authors.forename: Obinna N
authors.initials: ON
authors.lastname: Obianom
authors.affiliation: Department of Oral Maxillofacial Surgery, the First Affiliated Hospital, Xiangya Medical School, Central South University, Hunan 410007, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Su
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD, USA. Electronic address: yshu@rx.umaryland.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shu
mesh_terms: D001692:Biological Transport; D002104:Cadmium / Q000378:metabolism* / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D008687:Metformin / Q000378:metabolism / Q000494:pharmacology; D027701:Organic Cation Transport Proteins / Q000502:physiology*
chemical_list: D027701:Organic Cation Transport Proteins; D002104:Cadmium; D008687:Metformin
keywords: Cadmium; Detoxification; Kidney; Multidrug and toxin extrusion protein; Toxicity; Transporter