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 (Cd{sup 2+}). In this study, we aimed to examine whether Cd{sup 2+} 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 Cd{sup 2+}. The cells overexpressing MATEs showed a 2–4 fold increase of Cd{sup 2+} uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (K{sub m}) of 130 ± 15.8 μM for HEK-hMATE1; 139 ± 21.3 μM for HEK-hMATE2-K; and 88.7 ± 13.5 μM for HEK-mMate1, respectively. Cd{sup 2+} could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC{sub 50}) of 97.5 ± 6.0 μM, 20.2 ± 2.6 μM, and 49.9 ± 6.9 μM in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd{sup 2+} out ofmore »
- Authors:
-
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, MD (United States)
- Department of Oral Maxillofacial Surgery, the First Affiliated Hospital, Xiangya Medical School, Central South University, Hunan 410007 (China)
- Publication Date:
- OSTI Identifier:
- 22690891
- Resource Type:
- Journal Article
- Journal Name:
- Toxicology and Applied Pharmacology
- Additional Journal Information:
- Journal Volume: 314; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; ABUNDANCE; ANIMAL TISSUES; CADMIUM; CADMIUM IONS; DETOXIFICATION; EXTRUSION; KIDNEYS; MICE; PROTEINS; PUBLIC HEALTH; SUBSTRATES; TOXICITY; TOXINS; UPTAKE
Citation Formats
Yang, Hong, Guo, Dong, Obianom, Obinna N., Su, Tong, Polli, James E., and Shu, Yan. Multidrug and toxin extrusion proteins mediate cellular transport of cadmium. United States: N. p., 2017.
Web. doi:10.1016/J.TAAP.2016.11.007.
Yang, Hong, Guo, Dong, Obianom, Obinna N., Su, Tong, Polli, James E., & Shu, Yan. Multidrug and toxin extrusion proteins mediate cellular transport of cadmium. United States. https://doi.org/10.1016/J.TAAP.2016.11.007
Yang, Hong, Guo, Dong, Obianom, Obinna N., Su, Tong, Polli, James E., and Shu, Yan. 2017.
"Multidrug and toxin extrusion proteins mediate cellular transport of cadmium". United States. https://doi.org/10.1016/J.TAAP.2016.11.007.
@article{osti_22690891,
title = {Multidrug and toxin extrusion proteins mediate cellular transport of cadmium},
author = {Yang, Hong and Guo, Dong and Obianom, Obinna N. and Su, Tong and Polli, James E. and Shu, Yan},
abstractNote = {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 (Cd{sup 2+}). In this study, we aimed to examine whether Cd{sup 2+} 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 Cd{sup 2+}. The cells overexpressing MATEs showed a 2–4 fold increase of Cd{sup 2+} uptake that could be blocked by the MATE inhibitor cimetidine. A saturable transport profile was observed with the Michaelis-Menten constant (K{sub m}) of 130 ± 15.8 μM for HEK-hMATE1; 139 ± 21.3 μM for HEK-hMATE2-K; and 88.7 ± 13.5 μM for HEK-mMate1, respectively. Cd{sup 2+} could inhibit the uptake of metformin, a substrate of MATE transporters, with the half maximal inhibitory concentration (IC{sub 50}) of 97.5 ± 6.0 μM, 20.2 ± 2.6 μM, and 49.9 ± 6.9 μM in HEK-hMATE1, HEK-hMATE2-K, and HEK-mMate1 cells, respectively. In addition, hMATE1 could transport preloaded Cd{sup 2+} out of the HEK-hMATE1 cells, thus resulting in a significant decrease of Cd{sup 2+}-induced cytotoxicity. The present study has provided the first evidence supporting that MATEs transport Cd{sup 2+} and may function as cellular elimination machinery in Cd intoxication. - Highlights: • Cadmium is an environmentally prevalent toxicant. • Little was known regarding the elimination and detoxification of cadmium. • Cadmium ion is here demonstrated as a substrate of MATE transporters. • MATEs may function as cellular elimination machinery in cadmium detoxification.},
doi = {10.1016/J.TAAP.2016.11.007},
url = {https://www.osti.gov/biblio/22690891},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 314,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2017},
month = {Sun Jan 01 00:00:00 EST 2017}
}