Interactions of human organic anion as well as cation transporters with indoxyl sulfate
Interactions of human organic anion as well as cation transporters with indoxyl sulfate
复制标题
DOI：
10.1016/s0014-2999(03)01530-9
复制
发表时间：
2003-04-11
影响因子：
5
通讯作者：
Endou, H
中科院分区：
文献类型：
--
作者：
Enomoto, A;Takeda, M;Endou, H
包括硫酸吲哚酚在内的各种尿毒症毒物对尿毒症患者产生许多生物学效应。为了阐明硫酸吲哚酚在人体内药代动力学的分子机制，我们使用稳定的转染子研究了人有机阴离子转运蛋白（human-OAT）和人有机阳离子转运蛋白（human-OCT）与硫酸吲哚酚的相互作用。硫酸吲哚酚抑制人OAT 1、人OAT 3和人OAT 4，但不抑制人OAT 2、人OCT 1和人OCT 2。动力学分析显示，人OAT 1、人OAT 3和人OAT 4的Ki值分别为22.7、168.7和181.3 μ M。人OAT 1和人OAT 3介导硫酸吲哚酚的摄取，人OAT 4不仅介导硫酸吲哚酚的摄取，还介导硫酸吲哚酚的外排。总之，通过比较Ki值与未结合硫酸吲哚酚的血浆浓度，预测人OAT 1和人OAT 3介导硫酸吲哚酚的体内转运。此外，研究表明人OAT 1和人OAT 3参与硫酸吲哚酚的尿排泄、肾功能不全的加重和硫酸吲哚酚诱导的尿毒症脑病。(C)2003 Elsevier Science B. V.保留所有权利。
Various uremic toxicants including indoxyl sulfate exert a number of biological effects on uremic patients. In order to elucidate the molecular mechanisms for the pharmacokinetics of indoxyl sulfate in human, we examined the interactions of human organic anion transporters (human-OATs) and human organic cation transporters (human-OCTs) with indoxyl sulfate using stable transfectants. Indoxyl sulfate inhibited human-OAT1, human-OAT3 and human-OAT4, but not human-OAT2, hurnan-OCT1 and human-OCT2. Kinetic analysis revealed that the K-i values for human-OAT1, human-OAT3 and human-OAT4 were 22.7, 168.7 and 181.3 muM, respectively. Human-OAT1 and human-OAT3 mediated the uptake of indoxyl sulfate and human-OAT4 mediated not only the uptake but also the efflux of indoxyl sulfate. In conclusion, by comparing the Ki values with the plasma concentration of unbound indoxyl sulfate, it was predicted that human-OAT1 and human-OAT3 mediate the transport of indoxyl sulfate in vivo. In addition, it was suggested that human-OAT1 and human-OAT3 are involved in the urinary excretion of indoxyl sulfate, the exacerbation of renal dysfunction and the induction of uremic encephalopathy by indoxyl sulfate. (C) 2003 Elsevier Science B.V. All rights reserved.