Renal organic cation and nucleoside transport.
Renal organic cation and nucleoside transport.
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肾脏有机阳离子和核苷转运。
DOI：
10.1016/s0006-2952(02)01062-6
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发表时间：
2002
影响因子：
5.8
通讯作者：
Nelson,JArly
中科院分区：
文献类型：
--
作者：
Chen,Rong;Jonker,JohanW;Nelson,JArly
我们先前报道了大鼠有机阳离子转运蛋白rOCT1可以转运核苷类似物脱氧块菌素(DTub)(Chen R，Nelson JA.Biochem Pharmacol 2000；60：215-9)。阳离子形式的dTub(dTub+)似乎是rOCT1的真正底物。我们还报道，虽然rOCT2与rOCT1相似，但它在pH 7.4时不转运dTub。在这项研究中，我们测量了rOCT1和rOCT2在降低pH值(pH 5.4)下摄取dTub+的kmand Vmax。底物活性的差异在很大程度上是由于rOCT2对dTub+的亲和力较差。根据Vmax/Km值估算，rOCT2的转运效率仅为rOCT1的6%。在rOCT1和rOCT2之间构建的嵌合体表明，dTub结合的差异存在于跨膜区2-7。为了评估OCT1在肾脏分泌dTub中的潜力，我们测量了OCT1基因敲除小鼠的组织分布和尿中dTub的排泄量。基因敲除小鼠和野生型小鼠在肾脏排泄率、血浆dTub水平和组织分布方面没有显著差异。因此，dTub是OCT1的良好底物；然而，OCT1似乎不是其肾脏分泌所必需的。
We previously reported that the rat organic cation transporter rOCT1 could transport the nucleoside analog deoxytubercidin (dTub) (Chen R, Nelson JA. Biochem Pharmacol 2000;60:215–9). The cationic form of dTub (dTub+) appeared to be the true substrate of rOCT1. We also reported that although rOCT2 is similar to rOCT1, it does not transport dTub at pH 7.4. In this study, we measured the Kmand Vmaxvalues of dTub+uptake at a reduced pH (pH 5.4) for both rOCT1 and rOCT2. The difference in substrate activity appears due, in large part, to a poor affinity of rOCT2 for dTub+. The transport efficiency estimated by Vmax/Kmvalues for rOCT2 was only 6% that of rOCT1. Chimeras constructed between rOCT1 and rOCT2 revealed that the difference in dTub binding lies within transmembrane domains 2–7. To evaluate the potential of OCT1 in the renal secretion of dTub, tissue distribution and urinary excretion of dTub in OCT1 knockout mice were measured. No significant difference was observed in renal elimination, plasma level, and tissue distribution of dTub between the knockout and the wild-type mice. Therefore, dTub is a good substrate for OCT1; however, OCT1 does not appear to be necessary for its renal secretion.