Regulation of drug transporters by PDZ adaptor proteins and nuclear receptors.
Regulation of drug transporters by PDZ adaptor proteins and nuclear receptors.
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DOI：
10.1016/j.ejps.2005.11.006
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发表时间：
2006-04
期刊：
影响因子：
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通讯作者：
Y. Kato;Chizuru Watanabe;A. Tsuji
中科院分区：
文献类型：
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作者：
Y. Kato;Chizuru Watanabe;A. Tsuji
药物转运蛋白被认为参与了药物动力学的各个方面。药物转运体的鉴定和表征为我们理解药物处置以及药物相互作用和个体/物种间差异的分子机制提供了科学基础。另一方面，药物转运蛋白的调控机制仍然知之甚少，信息仅限于各种微粒体酶诱导剂对药物转运蛋白的诱导和下调。人们对直接与药物转运体相互作用的分子机制知之甚少。作为阐明这种分子机制的第一步，最近的研究发现了含有PDZ(PSD-95/Discs-Large/ZO-1)结构域的蛋白质，这些蛋白质直接与位于药物转运蛋白C末端的所谓PDZ结合基序相互作用。一些PDZ蛋白被认为至少通过两条途径调节转运蛋白，即在细胞表面稳定和直接调节转运蛋白功能。因此，治疗药物的膜转运可能不仅受药物转运体本身的控制，还可能间接受PDZ蛋白的影响。PDZ蛋白被归类为一个家族，其成员被认为具有不同的但也有多余的生理作用。这篇综述文章的目的是总结关于蛋白质相互作用和药物转运体功能调节的现有知识。
Drug transporters have been suggested to be involved in various aspects of pharmacokinetics. Identification and characterization of drug transporters have given us a scientific basis for understanding drug disposition, as well as the molecular mechanisms of drug interaction and inter-individual/inter-species differences. On the other hand, regulatory mechanisms of drug transporters are still poorly understood, and information is limited to induction and down-regulation of drug transporters by various microsomal enzyme inducers. Little is known about the molecular machinery that directly interacts with the drug transporters. As a first step to clarify such molecular mechanisms, recent studies have identified PDZ (PSD-95/Discs-large/ZO-1) domain-containing proteins that directly interact with the so-called PDZ binding motif located at the C-terminus of drug transporters. Some of the PDZ proteins have been suggested to regulate transporters via at least two pathways, i.e. stabilization at the cell-surface and direct modulation of transporter function. Therefore, it is possible that membrane transport of therapeutic agents is not only governed by the drug transporters themselves, but also indirectly by PDZ proteins. The PDZ proteins are classified as a family, the members of which are thought to have distinct, but also redundant physiological roles. The purpose of this review article is to summarize the available knowledge on protein interactions and functional modulation of drug transporters.