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Role of hepatic transporters in the detoxification

Research Project

Project/Area Number 09044267
Research Category

Grant-in-Aid for international Scientific Research

Allocation TypeSingle-year Grants
SectionJoint Research
Research Field Biological pharmacy
Research InstitutionGraduate School of Pharmaceutical Sciences, The University of Tokyo

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)

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)
Project Period (FY) 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥7,500,000 (Direct Cost: ¥7,500,000)
Fiscal Year 1997: ¥7,500,000 (Direct Cost: ¥7,500,000)
KeywordsABC transporter / cMOAT / MRP / MLP / multidrug resistance / biliary excretion / ABC輸送担
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.

Report

(2 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • Research Products

    (22 results)

All Other

All Publications (22 results)

  • [Publications] X.Y.Chu: "Multispecific organic anion transporter is responsible for the biliary excretion of the camotothecin derivative irinotecan and its metabolites inrats." J.Pharmacol.Exp.Ther.281. 304-314 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Niinuma: "Kinetic analysis of the primaryactive transport of conjugated metabolites across the bile canalicular membrane:Comparative study between DNP-SG(S-(2,4-dinitrophenyl)-glutathione)and E3040-glucuronide" J.Pharmacol.Exp.Ther.282. 866-872 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] X.Y.Chu: "Multiplicity of biliary excretion mechanisms for irinotecan,CPT-11,and its metabolites in rats" Cancer Res.57. 1934-1938 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Masuda: "Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter(cMOAT)in rats" Cancer Res.57. 3506-3510 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.C.Shin: "Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonistBQ-123" Am.J.Physiol.272. G976-G986 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Ito: "Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver" J.Biol.Chem. 273. 1684-1688 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 鈴木 洋史: "抗癌剤の相互作用" (医薬ジャーナル社)杉山 雄一,佐々木 康綱 編,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] 楠原 洋之: "抗癌剤の相互作用" (医薬ジャーナル社)杉山 雄一,佐々木 康綱 編,

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] X.-Y.Chu et al.: "Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats" J.Pharmacol.Exp.Therap.281. 304-314 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Niinuma et al.: "Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrane : comparative study of S- (2,4-dinitrophenyl) -glutathione and 6-hydroxy-5,7-dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole glucuronide" J.Pharmacol.Exp.Therap.282. 866-872 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] X.-Y.Chu et al.: "Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats" Cancer Res. 57. 1934-1938 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] M.Masuda et al.: "Methotrexate is excreated into the bile by canalicular multispecific organic anion transporter in rats" Cancer Res. 57. 3506-3510 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] H.C.Shin et al.: "Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonist BQ-123" Am.J.Physiol. (Gastrointest.Liver Physiol.). G979-G986 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] K.Ito et al.: "Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver" J.Biological Chemistry. 273. 1684-1688 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] X. Y. Chu: "Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats." J. Pharmacol. Exp. Ther.281. 304-314 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K. Niinuma: "Kinetic analysis of the primary active transport of conjugated metabolites across the bile canalicular membrae : Comparative study between DNP-SG (S-(2, 4-dinitrophenyl) -glutathione) and E3040-glucuronide" J. Pharmacol. Exp. Ther.282. 866-872 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] X. Y. Chu: "Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats" Cancer Res.57. 1934-1938 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] M. Masuda: "Methotrexate is excreted into the bile by canalicuiar multispecific organic anion transporter (cMOAT) in rats" Cancer Res.57. 3506-3510 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H. C. Shin: "Hepatobiliary transport mechanism for the cyclopentapeptide endothelin antagonist BQ-123" Am. J. Physiol.272. G976-G986 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] K. Ito: "Functional analysis of a canalicular multispecific organic anion transporter cloned from rat liver" J. Biol. Chem. 273. 1684-1688 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 鈴木 洋史: "抗癌剤の相互作用" (医薬ジャーナル社)杉山雄一、佐々木康網 編,

    • Related Report
      1997 Annual Research Report
  • [Publications] 楠原 洋之: "抗癌剤の相互作用" (医薬ジャーナル社)杉山雄一、佐々木康網 編,

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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