Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms
Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms
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DOI：
10.1152/ajprenal.00431.2009
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发表时间：
2010-04-01
影响因子：
4.2
通讯作者：
Kim, Richard B.
中科院分区：
文献类型：
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作者：
Schwabedissen, Henriette E. Meyer Zu;Verstuyft, Celine;Kim, Richard B.
Meyer zu Schwabedissen HE，Verstuyft C，Kroemer HK，Becquemont L，Kim RB.人多药和毒素外排1（MATE 1/SLC 47 A1）转运蛋白：功能表征、与OCT 2（SLC 22 A2）的相互作用和单核苷酸多态性。美国肾脏生理学杂志298：F997-F1005，2010年。首次发表于2010年1月6日; doi：10.1152/ajprenal.00431.2009。许多阳离子化合物的肾消除被认为是由有机阳离子转运蛋白2（OCT 2，SLC 22 A2）介导的，有机阳离子转运蛋白2是一种在肾小管细胞的基底外侧区域表达的药物摄取转运蛋白。最近，分泌有机阳离子的关键外排转运蛋白被确定为电中性H+/有机阳离子交换剂，称为多药物和毒素排出（MATE）型转运蛋白1（MATE 1，SLC 47 A1）。本研究的主要目的是评估肾脏阳离子转运蛋白OCT 2和MATE 1之间的相互作用以及人MATE 1遗传变异的功能评估。首先，使用重组牛痘表达系统测定各种试剂与OCT 2或MATE 1介导的转运相互作用的能力。我们能够确定几种药物在临床上使用的不同的抑制能力，这些转运。随后，我们使用OCT 2和MATE 1双转染细胞进一步评估了这些化合物对共享底物细胞蓄积的影响。与使用单一转运蛋白转染细胞获得的数据一致，表现出优先抑制MATE 1的化合物（如雷帕霉素和米托蒽醌）诱导阳离子底物的显著细胞蓄积。我们接下来评估了MATE 1基因多态性的功能相关性。二甲双胍和四乙铵转运活性的显著丧失见于两种非同义单核苷酸多态性（SNP），c. 404T>C（p.159T>M）和c. 1012 G>A（第338页V>A）。c.404T>C仅见于亚洲受试者，等位基因频率为1%，而c.1012G>A SNP更为常见，尤其是在非洲裔受试者中。总之，我们发现MATE 1与OCT 2的协调功能可能有助于有机阳离子药物的矢量肾消除，并且MATE 1的活性改变（无论是药物还是多态性）应被视为肾阳离子药物消除的重要决定因素。
Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB. Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol 298: F997-F1005, 2010. First published January 6, 2010; doi:10.1152/ajprenal.00431.2009.-renal elimination of a number of cationic compounds is thought to be mediated by the organic cation transporter 2 (OCT2, SLC22A2), a drug uptake transporter expressed at the basolateral domain of renal tubular cells. Recently, the key efflux transporter for the secretion organic cations was identified as an electroneutral H+/organic cation exchanger termed the multidrug and toxin extrusion (MATE)-type transporter 1 (MATE1, SLC47A1). The key goals of this study were to assess the interplay between the renal cationic transporters OCT2 and MATE1 and the functional assessment of genetic variation in human MATE1. First, the ability of various agents to interact with OCT2-or MATE1-mediated transport was determined using a recombinant vaccinia expression system. We were able to identify several drugs in clinical use with a divergent inhibitory capacity for these transporters. Subsequently, we further assessed the effect of those compounds on the cellular accumulation of shared substrates using OCT2 and MATE1 double-transfected cells. Consistent with data obtained using single transporter transfected cells, compounds that exhibited preferential inhibition of MATE1 such as rapamycin and mitoxantrone induced significant cellular accumulation of cationic substrates. We next assessed the functional relevance of MATE1 genetic polymorphisms. Significant loss of transport activity for metformin and tetraethylammonium was noted for two nonsynonymous single nucleotide polymorphisms (SNPs), c. 404T>C (p. 159T>M) and c. 1012G>A (p. 338V>A). The c.404T>C was only seen in Asian subjects with an allele frequency of 1%, and the c.1012G>A SNP was much more common, especially among those of African descent. In conclusion, we show that coordinate function of MATE1 with OCT2 likely contributes to the vectorial renal elimination of organic cationic drugs and that altered activity of MATE1, whether by drugs or polymorphisms, should be considered as an important determinant of renal cationic drug elimination.