MRP2-Mediated Reduced Glutathione Transport in Protection Against Oxidant Stress

Abstract

Although the primary physiological role of multidrug resistance-associated protein 2 (MRP2) appears to be the export of a wide variety of organic molecules from the cell, including glutathione disulfide (GSSG) and glutathione S-conjugates, there is now strong evidence that MRP2 also is able to export reduced glutathione (GSH) from the cell. The ability to export both GSH and GSSG would allow MRP2 to contribute directly to the regulation of the cellular thiol-redox status and therefore to the protection against oxidative stress. In addition, because GSH export is intimately linked to the other biological functions of this tripeptide, MRP2 may contribute to the regulation of these other cellular functions. Evidence for a role of MRP2 in GSH export comes from several studies, including (a) studies in MRP2-deficient rats demonstrating that these animals are unable to transport GSH into bile; (b) in vivo and in vitro studies demonstrating that cellular GSH export rates correlate with MRP2 expression levels; (c) comparative studies with the yeast orthologue of MRP2, Ycflp, showing that the yeast orthologue functions as an ATP-driven GSH transporter; (d) direct measurement of ATP-dependent GSH transport in rat liver canalicular membrane vesicles; and (e) studies with MRP1, the functional orthologue of MRP2, demonstrating that MRP1 is able to transport GSH. Taken together these data indicate that GSH is a substrate for MRP2; however, neither the precise biochemical mechanism of transport nor the quantitative significance of this process is yet known.