Oatp2 mediates bidirectional organic solute transport: A role for intracellular glutathione
Oatp2 mediates bidirectional organic solute transport: A role for intracellular glutathione
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DOI：
10.1124/mol.58.2.335
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发表时间：
2000-08-01
影响因子：
3.6
通讯作者：
Ballatori, N
中科院分区：
文献类型：
--
作者：
Li, LQ;Meier, PJ;Ballatori, N
OATP转运蛋白家族的成员之一，大鼠Oatp1，作为阴离子交换器，部分由谷胱甘肽(GSH)电化学梯度驱动，表明其他OATP相关转运蛋白也可能通过这一机制被激活。本研究检测了大鼠Oatp2是否也是一个阴离子交换器，如果是，它是否被GSH电化学梯度带电。与Oatp1一样，表达Oatp2的非洲爪哇卵母细胞对10muM[H-3]牛磺胆酸盐的摄取可被细胞内0.2 mM未标记牛磺胆酸盐反式刺激，表明其具有双向转运作用。有趣的是，谷胱甘肽、S-甲基谷胱甘肽、S-磺基邻苯二甲酸谷胱甘肽、S-二硝基苯基谷胱甘肽或邻苯二甲酸(谷胱甘肽类似物)也能反式刺激表达Oatp2的卵母细胞摄取[H-3]牛磺胆酸，但不受戊二酸或N-乙酰半胱氨酸的影响，这表明GSH衍生物及其结合物可能是Oatp2的胞内底物。在表达Oatp2的卵母细胞中，[H-3]GSH和[H-3]S-(2，4-二硝基苯基)-谷胱甘肽的外流增强为这一假说提供了支持。然而，与Oatp1相反，胞外GSH不能顺式抑制表达Oatp2的卵母细胞摄取[H-3]牛磺胆酸或[H-3]地高辛，表明细胞内高GSH浓度的刺激作用不是由于耦合交换机制所致。综上所述，这些结果表明Oatp2通过GSH敏感的促进扩散机制介导了有机阴离子的双向转运，并提示该转运蛋白可能在细胞内特定有机分子的输出中发挥作用。
One member of the OATP family of transporters, rat Oatp1, functions as an anion exchanger that is driven in part by the glutathione (GSH) electrochemical gradient, indicating that other OATP-related transporters may also be energized by this mechanism. The present study examined whether rat Oatp2 is also an anion exchanger, and, if so, whether it is energized by the GSH electrochemical gradient. As with Oatp1, uptake of 10 mu M [H-3]taurocholate in Oatp2-expressing Xenopus laevis oocytes was trans-stimulated by intracellular 0.2 mM unlabeled taurocholate, indicating bidirectional transport. Interestingly, [H-3]taurocholate uptake in Oatp2-expressing oocytes was also trans-stimulated when oocytes were preloaded with GSH, S-methylglutathione, S-sulfobromophthalein-glutathione, S-dinitrophenyl glutathione, or ophthalmic acid (a GSH analog) but not by glutarate or N-acetylcysteine, suggesting that GSH derivatives and conjugates may function as intracellular substrates for Oatp2. Support for this hypothesis was provided by the demonstration of enhanced [H-3]GSH and [H-3]S-(2,4-dinitrophenyl)-glutathione efflux in Oatp2-expressing oocytes. However, in contrast to Oatp1, extracellular GSH failed to cis-inhibit uptake of [H-3]taurocholate or [H-3]digoxin in Oatp2-expressing oocytes, indicating that the stimulatory effect of high intracellular GSH concentrations is not due to a coupled exchange mechanism. Taken together, the results indicate that Oatp2 mediates bidirectional transport of organic anions by a GSH-sensitive facilitative diffusion mechanism and suggest that this transporter may play a role in cellular export of specific organic molecules.