Role of SLC xenobiotic transporters and their regulatory mechanisms PDZ proteins in drug delivery and disposition.
Role of SLC xenobiotic transporters and their regulatory mechanisms PDZ proteins in drug delivery and disposition.
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DOI：
10.1016/j.jconrel.2006.06.009
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发表时间：
2006-11
期刊：
影响因子：
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通讯作者：
T. Sugiura;Y. Kato;A. Tsuji
中科院分区：
文献类型：
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作者：
T. Sugiura;Y. Kato;A. Tsuji
近年来，人们发现了多种外源性物质（或药物）转运蛋白，它们作为有毒物质的屏障和吸收营养物质进入体内的内流泵发挥着重要作用。由于这些外源性物质转运蛋白通常具有广泛的识别特异性，并接受各种类型的化合物作为底物，因此这些转运蛋白的定位和功能表达可能是影响治疗药物的处置和随后的生物活性的关键因素之一。药物转运蛋白的鉴定和表征为我们理解药物的递送和处置以及药物相互作用的分子机制和个体间/种间差异提供了科学依据。为了准确理解转运蛋白在体内的药理作用，阐明转运蛋白调控的分子机制也很重要。作为阐明这些转运蛋白的细胞表面表达和/或功能的调控机制的第一步，最近的研究集中在位于几种类型的外源性转运蛋白羧基端的PDZ（PSD-95/Discs-large/ZO-1）结合基序。大多数转运蛋白与PDZ结构域的蛋白直接相互作用的潜力，在肾脏和/或小肠上皮细胞的顶端膜上表达，这意味着这种蛋白质-蛋白质相互作用可能发挥作用的转运蛋白的顶端定位。在这篇简短的综述文章中，我们总结了转运蛋白及其调控机制在药物输送和处置中的重要性，重点介绍了转运蛋白介导的药物靶向的几个方面。
Various types of xenobiotic (or drug) transporters have been recently identified to play important roles as barriers against toxic compounds and influx pumps to take up nutrients into the body. Since those xenobiotic transporters generally have wide range of recognition specificity and accept various types of compounds as substrates, localization and functional expression of such transporters could be one of the critical factors that affect the disposition and subsequent biological activity of therapeutic agents. Identification and characterization of drug transporters have given us a scientific basis for understanding drug delivery and disposition, as well as the molecular mechanisms of drug interaction and inter-individual/inter-species differences. To precisely understand pharmacological roles of the transporters in the body, it is also important to clarify molecular mechanisms involved in regulation of the transporters. As a first step to clarify the regulatory mechanisms that govern cell-surface expression and/or function of these transporters, recent researches have focused on PDZ (PSD-95/Discs-large/ZO-1) binding motif localized on carboxylic terminus of several types of xenobiotic transporters. Most of the transporters showing direct interaction potential with the PDZ domain-containing proteins are expressed on apical membranes in epithelial cells of kidney and/or small intestine, implying that such protein–protein interaction may play a role in apical localization of the transporters. In this mini-review article, we summarize importance of transporters and their regulatory mechanisms in drug delivery and disposition, focusing on several aspects of transporter-mediated drug targeting.