MOLECULAR ORGANIZATION OF RENAL ORGANIC CATION TRANSPORT

肾脏有机阳离子转运的分子组织

• 批准号: 6381925
• 负责人: STEPHEN H WRIGHT
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381925
• 关键词: Xenopus oocyte; bioenergetics; cations; chemical kinetics; drug metabolism; human tissue; ion transport; laboratory rabbit; membrane transport proteins; molecular cloning; organic chemicals; renal tubular transport

Organic cations include a vast collection of pharmacologically important compounds. Indeed, drugs from a wide array of clinical classes-including antihistamines, skeletal muscle relaxants, antiarrythmics, and beta- adrenoceptor blocking agents-are organic cations (Ocs). The kidney plays a critical role in clearing these compounds from the body, thereby influencing their clinical effectiveness and posing the potential for undesirable interactions at the level of the excretory process. A general model of renal OC secretion has been in place for almost 20 years, but it does not include the molecular mechanisms of the processes involved and, therefore lacks the basis upon which to build a predictive model of the renal secretion of cationic drugs. The recent cloning of several 'candidate transporters' believed to play a role in renal OC transport )OCT1, OCT2, OCTN1, and OCTN2) makes possible development of a molecularly-based secretory model, provided that answers to several critical questions are obtained: (1) Where are these transporters expressed in the kidney; (2) How (mechanistically) do they contribute to OC secretion; and (3) What substrates are handled by each of the several (current) candidate transporters? Finally, (4) Can the ensemble behavior of these processes, based upon their measured characteristics, account for the secretory activity observed in proximal tubules? To answer these questions we have developed an experimental plan that will examine the above listed characteristics of the candidate transporters The approach involves comparison of results obtained with intact renal tubules with those obtained using single cloned transport proteins. The latter system permits examination of the properties of single transporters, while the former provides the only means to assess how the integrated activity of a suite of processes influences net transepithelial substrate movement. The cloned transporters will include the human orthologs of the four transporters and, also, the rabbit orthologs of each process. The latter set of observation will be used to validate use of the intact tubule systems we will employ to test a model of cationic drug secretion based upon the individual characteristics of each OC transporter. This study will be the first to offer an integrated view of the several processes that must work together to effect renal secretion of cationic drugs and thereby establish the necessary base for developing a therapeutically useful model of renal drug secretion.

有机阳离子包括大量重要的药理学化合物。事实上，临床范围广泛的药物——包括抗组胺药、骨骼肌松弛剂、抗心律失常药和肾上腺素受体阻滞剂——都是有机阳离子（Ocs）。肾脏在清除体内这些化合物方面起着关键作用，从而影响其临床疗效，并在排泄过程中产生潜在的不良相互作用。肾脏OC分泌的一般模型已经存在了近20年，但它没有包括所涉及过程的分子机制，因此缺乏建立阳离子药物肾脏分泌预测模型的基础。最近克隆了几个被认为在肾OC转运中起作用的“候选转运蛋白”（OCT1, OCT2， OCTN1和OCTN2），使基于分子的分泌模型的发展成为可能，前提是获得了几个关键问题的答案：(1)这些转运蛋白在肾脏中的何处表达；(2)它们如何（在机制上）促进OC的分泌；(3)几种（当前）候选转运蛋白分别处理哪些底物？最后，(4)基于测量到的特征，这些过程的整体行为能否解释近端小管中观察到的分泌活性？为了回答这些问题，我们制定了一个实验计划，将检查候选转运蛋白的上述特征，该方法包括将完整肾小管获得的结果与使用单个克隆转运蛋白获得的结果进行比较。后一种系统允许检查单个转运蛋白的特性，而前一种系统提供了唯一的方法来评估一套过程的综合活性如何影响经上皮底物的净运动。克隆的转运蛋白将包括四个转运蛋白的人类同源物，以及每个过程的兔子同源物。后一组观察结果将用于验证完整小管系统的使用，我们将采用基于每个OC转运体的个体特征来测试阳离子药物分泌模型。这项研究将首次对影响肾脏分泌阳离子药物的几个过程提供一个综合的观点，从而为开发一个治疗性的肾脏药物分泌模型奠定必要的基础。