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Am J Physiol Gastrointest Liver Physiol 279: G417-G425, 2000;
0193-1857/00 $5.00
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Vol. 279, Issue 2, G417-G425, August 2000

ATP-dependent GSH and glutathione S-conjugate transport in skate liver: role of an Mrp functional homologue

James F. Rebbeor1,4, Gregory C. Connolly1,4, John H. Henson2,4, James L. Boyer3,4, and Nazzareno Ballatori1,4

1 Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642; 2 Department of Biology, Dickinson College, Carlisle, Pennsylvania 17013; 3 Department of Medicine and Liver Center, Yale University School of Medicine, New Haven, Connecticut 06510; and 4 Mount Desert Island Biological Laboratory, Salsbury Cove, Maine 04672

Multidrug resistance-associated proteins 1 and 2 (Mrp1 and Mrp2) are thought to mediate low-affinity ATP-dependent transport of reduced glutathione (GSH), but there is as yet no direct evidence for this hypothesis. The present study examined whether livers from the little skate (Raja erinacea) express an Mrp2 homologue and whether skate liver membrane vesicles exhibit ATP-dependent GSH transport activity. Antibodies directed against mammalian Mrp2-specific epitopes labeled a 180-kDa protein band in skate liver plasma membranes and stained canaliculi by immunofluorescence, indicating that skate livers express a homologous protein. Functional assays of Mrp transport activity were carried out using 3H-labeled S-dinitrophenyl-glutathione (DNP-SG). DNP-SG was accumulated in skate liver membrane vesicles by both ATP-dependent and ATP-independent mechanisms. ATP-dependent DNP-SG uptake was of relatively high affinity [Michaelis-Menten constant (Km) = 32 ± 9 µM] and was cis-inhibited by known substrates of Mrp2 and by GSH. Interestingly, ATP-dependent transport of 3H-labeled S-ethylglutathione and 3H-labeled GSH was also detected in the vesicles. ATP-dependent GSH transport was mediated by a low-affinity pathway (Km = 12 ± 2 mM) that was cis-inhibited by substrates of the Mrp2 transporter but was not affected by membrane potential or pH gradient uncouplers. These results provide the first direct evidence for ATP-dependent transport of GSH in liver membrane vesicles and support the hypothesis that GSH efflux from mammalian cells is mediated by members of the Mrp family of proteins.

glutathione; canalicular transport; bile secretion


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