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.

我们试图为在肝脏中表达的几种类型的转运蛋白建立基因表达系统，其中可以进行有机化合物的肝胆管转运的功能分析。我们与Peter J. Meier博士合作，研究了有机阴离子转运蛋白在正弦膜上的贡献，例如OATP1和NTCP对几种有机阴离子的净肝摄取，通过比较转化剂和培养的老鼠肝细胞之间的运输活性。研究了众所周知，该底物多特异性有机阴离子转运蛋白转运蛋白（CMOAT）在几种阴离子化合物的左右极端中起主要作用，叶叶及其结构类似物以及具有阴离子的小胡椒的小胡椒剂的底物特异性被鉴定为Cmoin的新底物。有机阴离子对小管膜蔬菜的吸收在人类中表现出很大的个体差异。同样，血管紧张素转化酶抑制剂的胆道极端存在很大的物种差异，这归因于通过CMOAT通过膜转运的物种差异。目前的发现对于通过转运蛋白预测这些药物的药物相互作用在临床上应该很重要。我们研究了多药耐药性调节剂SDZ PSC 833对胆道极端极端化合物和药物的影响。使用Piet Borst博士赠予的P-糖蛋白表达系统的分析正在进行中。我们成功地将MRP3的cDNA与突变大鼠的肝脏分离出来，这些突变大鼠的肝脏在遗传上缺乏，并表征其底物特异性和运输特性，据报道MRP3赋予对某种类型的抗癌药物的抗性。目前的结果对于了解体内的排毒系统以及肿瘤应该很重要。