| Co-Investigator(Kenkyū-buntansha) |
KUME Kazuhiko Graduate School of Medicine, The Univ.of Tokyo Research Associate, 医学部, 助手 (30251218)
ITO Kiyomi Faculty of Pharmaceutical Sciences, Kitasato University Assistant Professor, 薬学部, 講師 (60232435)
KATO Yukio Graduate School of Pharm.Sci., The Univ.of Tokyo, Research Associate, 大学院・薬学系研究科, 助手 (30251440)
SUZUKI Hiroshi Graduate School of Pharm.Sci., The Univ.of Tokyo Assistant Professor, 大学院・薬学系研究科, 助教授 (80206523)
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| Research Abstract |
Liver, along with kidney, plays an important role in the detoxification of xenobiotics. It is well established that drugs in the circulating blood are taken up into the liver via transporters on the basal membrane, and then excreted into the bile via transporters on the bile canalicular membrane. Concerning the transporters responsible for the uptake, Na^+-dependent bile acid transporter (Ntcp) and organic anion transporter 1 (oatp1) have been identified. However, no quantitative studies have been performed on the contribution of these transporters to the hepatic uptake of drugs. In the present study, we determined the contribution of each transporter in hepatic drug uptake, by comparing the ability to take up drugs into hepatocytes and into cDNA-transfected mammalian cells. The results suggested the presence of multiplicity for both Na^+-dependent and independent transport systems. Studies are under way to determine the contribution of homologous transporters (such as oatp2 and oat 3)
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. Concerning the transport across the bile canalicular membrane, the transport properties of organic anions has been identified by using the isolated bile canalicular membrane vesicles isolated from rats and humans. In addition, we have characterized the transport properties of canalicular multispecific organic anion transporter (cMOAT) using the membrane vesicles isolated from cDNA-transfected cells. Moreover, as a homologue of cMOAT, we have cloned rat and human MRP3 (multidrug resistance associated protein 3). Studies with isolated membrane vesicles from mammalian cells transfected with MRP3 cDNA, it was demonstrated that MRP3 accepts glucuronides, but not glutathione-conjugates, as good substrates. Thus, the difference in the transport characteristics was demonstrated between MRP1/2 and 3. In rats and HepG2 cells in culture, MRP3 was induced by phenobarbital, suggesting that the difference in the expression level of MRP3 may result in the interindividual difference in the ability to excrete xenobiotics and/or their conjugates into the bile in humans. Less
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