权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular diversity of organic ion transporters and their roles in the renal drug excretion

有机离子转运蛋白的分子多样性及其在肾脏药物排泄中的作用

基本信息

批准号：
11470495
负责人：
INUI Ken-ichi
金额：
$ 9.41万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

We have studied the structure, function and tubular localization of organic ion transporters expressed in the kidney to systematically elucidate the mechanisms of renal excretion process of ionic drugs.1. Organic cation transporter family : We demonstrated that OCT1 and OCT2 organic cation transporters recognized a variety of cationic drugs with similar substrate affinity. Immunocytochemical studies revealed that OCT1 and OCT2 were localized at the basolateral membrane of different tubular segments in the kidney. In addition, we found that the expression of OCT2, but not OCT1 and OCT3, was higher in the male kidney than the female kidney, and that the gender difference in OCT2 expression was regulated by sex hormones.2. Organic anion transporter family : We have characterized the substrate specificity of organic anion transporters, OAT1 and OAT-K1, using various heterologous expression systems. OAT1 recognized relatively hydrophilic organic anions, while OAT-K1 transports hydrophobic organic anions. We demonstrated that OAT1-mediated transport of methotrexate was competitively inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin and salicylate, suggesting that OAT1 is the major site of the transporter-mediated interaction between methotrexate and NSAIDs. In addition, we succeeded in cloning of a new organic anion transporter, OAT-K2. Functional analysis indicated that OAT-K2 also recognized a variety of hydrophobic organic anions like OAT-K1.These observations will help us to evaluate and predict the renal drug excretion. In addition, estimation of substrate affinity for each transporter could be useful to predict transporter-mediated drug interactions.

我们研究了肾脏中表达的有机离子转运体的结构、功能和小管定位，以系统地阐明离子药物在肾脏排泄过程中的机制。有机阳离子转运蛋白家族：我们证明了OCT1和OCT2有机阳离子转运蛋白可以识别多种具有相似底物亲和力的阳离子药物。免疫细胞化学研究显示，OCT1和OCT2定位于肾不同小管段的基底外侧膜。另外，我们发现OCT2在男性肾脏中的表达高于女性肾脏，而OCT1和OCT3的表达不高于男性肾脏，并且OCT2表达的性别差异受性激素的调节。有机阴离子转运蛋白家族：我们利用不同的异源表达系统表征了有机阴离子转运蛋白OAT1和OAT-K1的底物特异性。OAT1识别相对亲水的有机阴离子，而OAT-K1传输疏水的有机阴离子。我们证明了OAT1介导的甲氨蝶呤转运被吲哚美辛和水杨酸等非甾体抗炎药竞争性地抑制，这表明OAT1是转运体介导的甲氨蝶呤和非甾体抗炎药相互作用的主要位点。此外，我们成功克隆了一个新的有机阴离子转运蛋白OAT-K2。功能分析表明，OAT-K2也像OAT-K1一样识别多种疏水有机阴离子。这些观察结果将有助于我们评估和预测肾脏药物排泄。此外，估计底物对每种转运体的亲和力可能有助于预测转运体介导的药物相互作用。