Roles of MRP2 and oatp1 in Hepatocellular Export of Reduced Glutathione

ABSTRACT

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, oatp1 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.

KEY WORDS

glutathione - multidrug resistance-associated protein - organic anion transporting protein