Excretion of GSSG and glutathione conjugates mediated by MRP1 and cMOAT/MRP2.
It has been shown that both multidrug resistance-associated protein (MRP1) and canalicular multispecific organic anion transporter (cMOAT/MRP2) have the ability to extrude glutathione conjugates (GS-X pump activity)from cells. Therefore, they play an important role in the detoxification of xenobiotics. Using mrp1-knockout mice, it has recently been shown that MRP1/mrp1 has an important role in the export of leukotriene C4 (LTC4), a mediator of inflammation, and in protecting the body from a number of toxins, including several antitumor drugs. A comparison of the transport properties across the bile canalicular membrane in normal and mutant rats, whose cMOAT function is hereditarily defective, has shown that the physiologic role of cMOAT is to excrete LTC4, bilirubin glucuronides, 171-estradiol-170-D-glucuronide, and reduced folates. In the present review article, we summarize the substrate specificity and mechanism for the transport of these GS-X pumps, focusing on the pharmacologic and physiologic aspects. The transport activity mediated by cMOAT is also discussed in terms of a comparison between membrane vesicles from hepatocytes and cMOAT-transfected cells, and we also briefly examine the possible role of MRPI and cMOAT in the extrusion of reduced glutathione.
Suzuki
H
H
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.
Sugiyama
Y
Y
D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D019803:Glutathione Disulfide / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins
D018528:ATP-Binding Cassette Transporters; D027321:Anion Transport Proteins; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D019803:Glutathione Disulfide; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C086860:glutathione transporter