1997 Fiscal Year Final Research Report Summary
Role of hepatic transporters in the detoxification
| Project/Area Number |
09044267
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
Biological pharmacy
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| Research Institution | Graduate School of Pharmaceutical Sciences, The University of Tokyo |
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Principal Investigator |
SUGIYAMA Yuichi Graduate School of Pharm.Sci., The Univ.of Tokyo Professor, 大学院・薬学系研究科, 教授 (80090471)
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| Co-Investigator(Kenkyū-buntansha) |
COLE Susan P.C. Cancer Research Laboratories, Queen's University Professor, 医学部, 教授
KAPLOWITZ Neil Department of Medicine, University of South California Professor, 医学部, 教授
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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| Project Period (FY) |
1997
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| Keywords | ABC transporter / cMOAT / MRP / MLP / multidrug resistance / biliary excretion |
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| Research Abstract |
It is established that many organic anions including glucuronide and glutathione conjugates are excreted into the bile across the canalicular membrane via a primary active transporter referred to as canalicular multispecific organic anion transporter (cMOAT). In the present study, we clarified the substrate specificity of cMOAT by comparing the transport properties in normal and mutant rats (Eisai hyperbilirubinemic rats ; EHBR) whose cMOAT function is hereditarily defective. Since it has been established that the substrate specificity of cMOAT resembles that of multidrug resistance associated protein (MRP), we examined the substrate specificity of cMOAT,particularly focusing on the transport of antitumor reagents. We found that cMOAT accepts the following compounds ; methotrexate, carboxylate forms of CPT-11 (a topoisomerase inhibitor) and its reactive metabolite (SN-38), along with the glucuronide conjugate of SN-38. These results suggest that the tumor cells overexpressing cMOAT/MRP should acquire resistance against these chemotherapeutic reagents. Moreover, we had examined the function of cloned cMOAT cDNA by preparing the stable transfectant. ATP-dependent uptake of 2,4-dinitrophenyI-S-glutathione, a typical substrate for cMOAT,into membrane vesicles isolated from NIH/3T3 cells was stimulated by transfection of rat cMOAT cDNA This is the first direct demonstration that the cloned cMOAT cDNA has a function to transport organic anions. These results indicate that the membrane vesicles from the transfectant should be an excellent tool for the screening of chemotherapeutic reagents which cannot be the substrate for cMOAT/MRP.
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