Ballatori N, Rebbeor J F
Department of Environmental Medicine, University of Rochester School of Medicine, New York 14642, USA.
Semin Liver Dis. 1998;18(4):377-87. doi: 10.1055/s-2007-1007171.
Transport of reduced glutathione (GSH) into the extracellular space is the initial and perhaps limiting step in the turnover of the tripeptide in all mammalian cells; however, the transport system or systems that mediate GSH efflux remain obscure. In the liver, a major site of GSH synthesis, GSH is released at high rates into both blood plasma and bile. Nearly half of the GSH released by rat hepatocytes is transported across the canalicular membrane into bile, with biliary GSH concentrations reaching 8 to 10 mM. GSH transport into bile functions as a driving force for bile secretion and plays an important role in hepatic detoxification of drugs, metals, and other reactive compounds of both endogenous and exogenous origin. The remainder of the GSH is released across the sinusoidal membrane into blood plasma for delivery to other tissues. The molecular mechanisms of GSH efflux have not been identified for any cell type, although recent studies provide important insight into possible mechanisms. In particular, oatp1, the sinusoidal organic solute transporter, was recently shown to function as a GSH/organic solute exchanger. This finding identifies both the energy coupling mechanism for oatp1 and a pathway for GSH release into blood plasma. However, oatp probably only accounts for a fraction of the total GSH released into sinusoidal blood. A candidate canalicular GSH transport mechanism has also recently been described. Canalicular GSH efflux may be mediated by the adenosine 5'-triphosphate (ATP)-dependent organic solute transport protein MRP2 (also termed cMOAT or cMRP). MRP2 is a member of the multidrug resistance-associated family of proteins (MRP) whose preferred substrates include glutathione S-conjugates. Recent studies suggest that MRP can also transport GSH itself. This report summarizes the evidence documenting a role for oatp1 and MRP2 in GSH efflux from hepatocytes, and their possible contribution to hepatic GSH homeostasis.
还原型谷胱甘肽（GSH）转运至细胞外空间是所有哺乳动物细胞中三肽周转的起始步骤，可能也是限速步骤；然而，介导GSH外排的一个或多个转运系统仍不清楚。在肝脏这个GSH合成的主要部位，GSH以高速率释放到血浆和胆汁中。大鼠肝细胞释放的GSH近一半通过胆小管膜转运到胆汁中，胆汁中GSH浓度可达8至10 mM。GSH转运到胆汁中是胆汁分泌的驱动力，并且在肝脏对药物、金属以及内源性和外源性来源的其他反应性化合物的解毒过程中发挥重要作用。其余的GSH通过肝血窦膜释放到血浆中，以便输送到其他组织。尽管最近的研究为可能的机制提供了重要见解，但尚未确定任何细胞类型中GSH外排的分子机制。特别是，肝血窦有机溶质转运体oatp1最近被证明可作为GSH/有机溶质交换体发挥作用。这一发现确定了oatp1的能量偶联机制以及GSH释放到血浆中的途径。然而，oatp可能仅占释放到肝血窦血液中总GSH的一小部分。最近还描述了一种可能的胆小管GSH转运机制。胆小管GSH外排可能由依赖三磷酸腺苷（ATP）的有机溶质转运蛋白MRP2（也称为cMOAT或cMRP）介导。MRP2是多药耐药相关蛋白家族（MRP）的成员，其首选底物包括谷胱甘肽S-共轭物。最近的研究表明，MRP也可以转运GSH本身。本报告总结了证明oatp1和MRP2在肝细胞GSH外排中的作用及其对肝脏GSH稳态可能贡献的证据。
