Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1).
Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1).
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发表时间：
2000-03
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通讯作者：
M. Dresser;Andrew T. Gray;K. Giacomini
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作者：
M. Dresser;Andrew T. Gray;K. Giacomini
有机阳离子转运蛋白在临床药物、有毒物质和内源性化合物的吸收、分布和消除中发挥着重要作用。据报道，在肾脏制剂中，不同物种之间有机阳离子转运的功能特征存在显着差异。然而，造成这些种间差异的潜在分子机制尚不清楚。本研究的目的是确定小鼠、大鼠、兔子和人类有机阳离子转运蛋白 (OCT1) 同系物的动力学和底物选择性，这可能导致肾脏和肝脏处理有机阳离子的种间差异。通过一系列正四烷基铵 (nTAA) 化合物，观察到烷基链长度的增加与四种 OCT1 同系物的亲和力之间存在相关性。然而，物种同系物之间的表观亲和力常数 (K(i)) 不同。对于小鼠同源物 mOCT1，表观 K(i) 值范围为四丁基铵的 7 µM 至四甲基铵的 2000 µM。相比之下，人类同源物 hOCT1 与 nTAA 化合物的相互作用较弱。电压钳位卵母细胞的反刺激研究和电流测量表明，较大的 nTAA 化合物在表达 hOCT1 的卵母细胞中以更高的速率转运，而较小的 nTAA 在表达 mOCT1 或 rOCT1 的卵母细胞中以更高的速率转运。与啮齿动物和人类对应物相比，兔同源物 rbOCT1 在与 nTAA 相互作用方面表现出中间特性。该报告表明，人类 OCT1 同源物具有与啮齿动物和兔子 OCT1 同源物不同的功能特性。该研究强调了将动物模型临床前研究数据外推到人类的潜在困难。
Organic cation transporters play an important role in the absorption, distribution, and elimination of clinical agents, toxic substances, and endogenous compounds. In kidney preparations, significant differences in functional characteristics of organic cation transport between various species have been reported. However, the underlying molecular mechanisms responsible for these interspecies differences are not known. The goal of this study was to determine the kinetics and substrate selectivities of organic cation transporter (OCT1) homologs from mouse, rat, rabbit, and human that may contribute to interspecies differences in the renal and hepatic handling of organic cations. With a series of n-tetraalkylammonium (nTAA) compounds, a correlation between increasing alkyl chain length and affinity for the four OCT1 homologs was observed. However, the apparent affinity constants (K(i)) differed among the species homologs. For the mouse homolog mOCT1, apparent K(i) values ranged from 7 microM for tetrabutylammonium to 2000 microM for tetramethylammonium. In contrast, the human homolog hOCT1 exhibited weaker interactions with the nTAA compounds. Trans-stimulation studies and current measurements in voltage-clamped oocytes demonstrated that larger nTAA compounds were transported at greater rates in oocytes expressing hOCT1, whereas smaller nTAAs were transported at greater rates in oocytes expressing mOCT1 or rOCT1. The rabbit homolog rbOCT1 exhibited intermediate properties in its interactions with nTAAs compared with its rodent and human counterparts. This report demonstrates that the human OCT1 homolog has functional properties distinct from those of the rodent and rabbit OCT1 homologs. The study underscores potential difficulties in extrapolating data from preclinical studies in animal models to humans.