Multidrug and toxin extrusion proteins mediate cellular transport of cadmium.
Multidrug and toxin extrusion proteins mediate cellular transport of cadmium.
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DOI：
10.1016/j.taap.2016.11.007
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发表时间：
2017-01-01
影响因子：
3.8
通讯作者：
Shu, Yan
中科院分区：
文献类型：
--
作者：
Yang, Hong;Guo, Dong;Obianom, Obinna N.;Su, Tong;Polli, James E.;Shu, Yan
镉（Cd）是一种环境中普遍存在的有毒物质，对全球人类健康构成越来越大的风险。与Cd组织积累的广泛研究相比，对Cd的消除，特别是其毒性形式Cd离子（Cd 2+）的了解甚少。在这项研究中，我们的目的是检查是否镉+是一个底物的多药和毒素挤出蛋白（MATE），是重要的肾脏异生物质消除。使用过表达人MATE 1（HEK-hMATE 1）、人MATE 2-K（HEK-hMATE 2-K）和小鼠Mate 1（HEK-mMate 1）的HEK-293细胞研究Cd 2+的细胞转运和毒性。过表达MATE的细胞表现出2 - 4倍的Cd 2+摄取增加，这可以被MATE抑制剂西咪替丁阻断。观察到可饱和转运特征，HEK-hMATE 1的米氏常数（Km）分别为130 ± 15.8 μM; HEK-hMATE 2-K为139 ± 21.3 μM; HEK-mMate 1为88.7 ± 13.5 μM。Cd 2+可抑制二甲双胍（MATE转运蛋白的底物）的摄取，在HEK-hMATE 1、HEK-hMATE 2-K和HEK-mMate 1细胞中的半数最大抑制浓度（IC 50）分别为97.5 ± 6.0 μM、20.2 ± 2.6 μM和49.9 ± 6.9 μM。此外，hMATE 1可以将预先装载的Cd 2+转运出HEK-hMATE 1细胞，从而显著降低Cd 2+诱导的细胞毒性。本研究提供了第一个证据，支持MATEs转运Cd 2+，并可能作为细胞消除机制在镉中毒。
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 ± 15.8 μM for HEK-hMATE1; 139 ± 21.3 μM for HEK-hMATE2-K; and 88.7 ± 13.5 μM 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 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 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.
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影响因子：
2.1
作者：
Kajiwara, Moto;Masuda, Satohiro;Inui, Ken-ichi
通讯作者：
Inui, Ken-ichi
影响因子：
3.5
作者：
Soodvilai, Sunhapas;Nantavishit, Jiriporn;Chatsudthipong, Varanuj
通讯作者：
Chatsudthipong, Varanuj
影响因子：
10.4
作者：
Tellez-Plaza M;Navas-Acien A;Menke A;Crainiceanu CM;Pastor-Barriuso R;Guallar E
通讯作者：
Guallar E
影响因子：
4.5
作者：
Kimura, O;Endo, T;Sakata, M
通讯作者：
Sakata, M
影响因子：
3.8
作者：
Lee, Wing-Kee;Torchalski, Blazej;Thevenod, Frank
通讯作者：
Thevenod, Frank