Role of hepatic transporters in the detoxification

肝脏转运蛋白在解毒中的作用

基本信息

批准号：
10044243
负责人：
SUGIYAMA Yuichi
金额：
$ 4.48万
依托单位：
Graduate School of Pharmaceutical Sciences, The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

We attempted to establish gene expression system for several types of transporters expressed in the liver, in Which the functional analyses of the hepatobiliary transport of organic compounds can be performed. We collaborated with Dr. Peter J. Meier and investigated the contribution of organic anion transporters on the sinusoidal membrane such as oatp1 and Ntcp to the net hepatic uptake of several kinds of organic anions by comparing the transport activity between transfectant and cultured rat hepatocytes. The substrate specificity of canalicular multispecific organic anion transporter (cMOAT) which is known to play a predominant role in the biliay excretion of several anionic compounds was investigated and folates and its structural analogues as well as small peptides with anionic moiety were identified as new substrates of cMOAT. The uptake of organic anions into canalicular membrane vesicles exhibits a large interindividual difference in humans. Also, there is a large species difference in the biliary excretion of an angiotensin converting enzyme inhibitor, which is attributed to the species difference in the membrane transport via cMOAT. The present findings should be clinically important for the prediction of drug-drug interactions of these drugs via the transporters. We investigated the effect of a multidrug resistance modulator, SDZ PSC 833 on the biliary excretion of endogenous compounds and drugs. The analysis using P-glycoprotein expression system gifted from Dr. Piet Borst is being carried out. We succeeded to isolate cDNA of MRP3 from the liver of mutant rats which cMOAT is hereditarily deficient, and to characterize its substrate specificity and transport property, ・ MRP3 is reported to confer resistance to a certain type of anticancer drugs. The present results should be important to understand the detoxification system in the body and also tumors.

我们尝试建立几种在肝脏中表达的转运蛋白的基因表达系统，在该系统中可以对有机化合物的肝胆转运进行功能分析，我们与Peter J. Meier博士合作，研究了有机阴离子转运蛋白的贡献。通过比较转染子和培养的大鼠肝细胞之间的转运活性，研究oatp1和Ntcp等肝窦膜上对几种有机阴离子的净摄取。多特异性有机阴离子转运蛋白 (cMOAT) 已知在多种阴离子化合物的双排泄中起主要作用，对此进行了研究，并鉴定了叶及其结构类似物以及带有阴离子部分的小肽作为 cMOAT 的新底物。进入胆管膜囊泡的有机阴离子在人类中表现出很大的个体差异，并且胆汁排泄也存在很大的物种差异。血管紧张素转换酶抑制剂，这归因于通过 cMOAT 的膜转运的物种差异。目前的发现对于预测这些药物通过转运蛋白的药物相互作用具有重要的临床意义。 , SDZ PSC 833 对内源性化合物和药物的胆汁排泄的影响我们正在使用 Piet Borst 博士赠送的 P-糖蛋白表达系统成功分离出 cDNA。 MRP3 来自 cMOAT 遗传性缺陷的突变大鼠的肝脏，为了表征其底物特异性和转运特性，据报道，MRP3 赋予对某种类型抗癌药物的耐药性。目前的结果对于了解体内的解毒系统非常重要。身体，还有肿瘤。