Roles of transporter adaptors as regulatory mechanism for drug absorption and disposition

转运蛋白适配器作为药物吸收和处置调节机制的作用

• 批准号: 18590137
• 负责人: KATO Yukio
• 金额: $ 2.53万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590137/
• 关键词: Transporter; Pharmacokinetics; Adaptor; Protein-protein interaction; Membrane permeation; Gastrointestinal absorption; Small intestine; Finical membrane; タンパク質問相互作用; 薬効・毒性; 機能制御

Many types of xenobiotic transporters have been identified. They generally exhibit multispecific recognition of various types of substrates, and mediate membrane permeation of therapeutic agents, thereby playing important roles in drug absorption and disposition. We have recently proposed that protein-protein interactions involving the xenobiotic transporters may affect their function, localization and expression on plasma membranes based on in vitro experimental data. So-called adaptor proteins that directly interact with the transporters include PDZ (PSD95, Dig and ZOO domain-containing proteins. This project was performed with an aim to clarify pharmacokinetic roles of such adaptor proteins in vivo. Using pdzk1 gene knockout (pdzk1^+) mice, it was found that interaction with a PDZ adaptor PDZK1 is essential for the cell-surface localization of three solute carriers, Slc15a1 (oligopeptide transporter PEPTD, S1c22a5 (carnitine/organic cation transporter OCTN2) and Slco 1a (organic ani … More on transporting polypeptide, OATP1A) in mouse small intestine. Electron microscopy revealed localization of PEPT1 in intracellular vesicular structures in pdzk1^+ mice. In pdzk1^+ mice, gastrointestinal absorption of cephalexin, a substrate of PEPT1 and carnitine, a substrate of OCTN2 was delayed, compared with wild mice. In addition, uptake of estrone sulfate, a substrate of OATP1A from apical membrane of small intestine was also decreased in pdzk1^+ mice. Thus, PDZK1 plays pivotal roles as a regulator of transporters, thereby affecting the absorption of substrates of those interacting transporters. Since PDZ adaptors have multiple PDZ domains in their structure, and each PDZ domain can interact with the cytosolic region of the transporters, it can be speculated that transporters are localized within networks consisting of several transporters and adaptors. We have also found that apical localization of PEPT1 and Slc5a1 (sodium/glucose cotransporter, SGLT1) was almost completely reduced in gene knockout mice for small GTP-binding protein rab8 (rab8^+). Gastrointestinal uptake across the apical membranes of glycylsarcosine, a substrate of PEPT1 and α-methylglucose, a substrate of SGLT1 was concomitantly reduced in rab8^+. Thus, our results demonstrate that rab8 is necessary for the proper localization of the two transporters and digestion of various nutrients which are the substrate of those transporters. Less

已经确定了许多类型的异生物转运蛋白。他们通常暴露了对各种类型底物的多特异性识别，并介导了治疗剂的膜渗透，从而在药物滥用和处置中发挥了重要作用。我们最近提出，涉及异种生物转运蛋白的蛋白质 - 蛋白质相互作用可能会影响其基于体外实验数据的质膜上的功能，定位和表达。与转运蛋白直接相互作用的所谓衔接蛋白包括PDZ（PSD95，DIG和动物园结构域的蛋白质。该项目的执行旨在澄清体内此类适配器蛋白的药代动力学作用。使用PDZK1基因敲除（PDZK1^+）敲除（PDZK1^+）Metaction，它是PDZ的ITS Acteraction pd pd pd pd，三个固体载体SLC15A1（寡肽转运蛋白PEPTD，S1C22A5（肉碱/有机有机阳离子转运蛋白octn2）和SLCO 1A（有机ANI）（更多关于在小鼠小型Intestine。 PDZK1+小鼠。这是PDZK1作为转运蛋白的调节剂的关键作用，从而影响了这些相互作用转运蛋白的底物的苦难。由于PDZ适配器在其结构中具有多个PDZ域，并且每个PDZ域都可以与转运蛋白的胞质区域相互作用，因此可以推测转运蛋白位于由几个转运蛋白和贴轴组成的网络中。我们还发现，对于小的GTP结合蛋白Rab8（rab8^+）的基因基因敲除小鼠，PEPT1和SLC5A1（钠/葡萄糖共转运蛋白，SGLT1）的根尖定位几乎被完全降低。在Rab8^+中，SGLT1的底物同时降低了SGLT1的底物，SGLT1的底物跨糖基盐的顶膜的胃肠道摄取。这是我们的结果表明，Rab8对于两个转运蛋白的正确定位和各种营养素的消化是必要的，这些营养素是这些转运蛋白的底物。较少的

项目成果

マウス小腸における有機アニオン性薬物estrone-3-sulfateのOatp介在吸収

Oatp介导的有机阴离子药物雌酮-3-硫酸酯在小鼠小肠中的吸收

• 发表时间: 2007
• 作者: 大竹 亨、加藤将夫、辻 彰;ほか
• 通讯作者: ほか

トランスポータータンパク質相互作用と活性調節創薬動態-医薬品創製のための考え方と最新情報-

转运蛋白相互作用和活性调节药代动力学 - 药物发现的概念和最新信息 -

• 发表时间: 2006
• 作者: Yukio;Kato;Yoshiyuki;Kubo;Akira;Tsuji;加藤将夫
• 通讯作者: 加藤将夫

Transporter-mediated hepatic uptake of ulifloxacin, an active meabolite of a prodrug-type new quinolone antibiotic prulifloxacin in rats.

转运介导的肝脏对乌利沙星的摄取，乌利沙星是大鼠体内前药型新型喹诺酮抗生素普利沙星的活性代谢物。

• 发表时间: 2007
• 期刊: Drung Metab Pharmacokinet 22
• 作者: Yagi Y;Aoki M;Kato Y;Tsuji A;ほか
• 通讯作者: ほか

Transporter-mediated hepatic uptake of ulifloxacin,an active metabolite of a prodrug-type new quinolone antibiotic prulifloxacin in rats

转运蛋白介导的大鼠肝脏对乌利沙星的摄取，乌利沙星是一种前药型新型喹诺酮抗生素普利沙星的活性代谢物

• 发表时间: 2007
• 期刊: Drug Metab Pharmacokinet 22
• 作者: Yagi Y;Aoki M;Iguchi M;Shibasaki S;Kurosawa T;Kato Y;Tsuji A
• 通讯作者: Tsuji A

Mutation in an adaptor protein PDZK1 affects transport activity of organic cation transporter OCTNs and oligopeptide transporter PEPT2.

接头蛋白 PDZK1 的突变会影响有机阳离子转运蛋白 OCTN 和寡肽转运蛋白 PEPT2 的转运活性。

• 发表时间: 2006
• 期刊: Drug Metab. Pharmacokinet. 21(5)
• 作者: Sugiura T;Kato Y;Tsuji A ほか
• 通讯作者: Tsuji A ほか