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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.

我们尝试建立几种肝脏转运蛋白的基因表达系统，并在此系统中进行有机物肝胆转运的功能分析。我们与Peter J. Meier博士合作，通过比较转染子和培养的大鼠肝细胞之间的转运活性，研究了窦状膜上的有机阴离子转运蛋白（如oatp 1和Ntcp）对几种有机阴离子的净肝摄取的贡献。研究了微管多特异性有机阴离子转运蛋白（cMOAT）的底物特异性，发现叶酸及其结构类似物和含阴离子基团的小肽是cMOAT的新底物。在人类中，小管膜囊泡对有机阴离子的吸收表现出很大的个体差异。此外，血管紧张素转换酶抑制剂的胆汁排泄存在较大的种属差异，这归因于通过cMOAT进行膜转运的种属差异。本研究结果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。我们研究了多药耐药调节剂SDZ PSC 833对内源性化合物和药物的胆汁排泄的影响。正在使用Piet Borst博士赠送的P-糖蛋白表达系统进行分析。我们成功地从cMOAT遗传缺陷的突变大鼠的肝脏中分离了MRP 3的cDNA，并表征了其底物特异性和转运性质。目前的结果应该是重要的，以了解体内的解毒系统，也肿瘤。