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Analysis of the mechanism for the development of cholestasis induced by the altered function of efflux transporters

Research Project

Project/Area Number 13470484
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionThe University of Tokyo

Principal Investigator

SUZUKI Hiroshi  The University of Tokyo, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学系研究科, 助教授 (80206523)

Co-Investigator(Kenkyū-buntansha) SHODA Jun-ichi  Tsukuba University Department of Internal Medicine, Lecturer, 臨床医学系, 講師 (90241827)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥9,100,000 (Direct Cost: ¥9,100,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥6,000,000 (Direct Cost: ¥6,000,000)
Keywordsbiliary excretion / transcellular transport / vectorial transport / ABC transporter / MRP2 / ABCC2 / MRP3 / ABCC3 / bile acids / トランスポーター / BSEP / 胆汁うっ滞 / 内在化
Research Abstract

Multidrug resistance associate protein 2 (MRP2/ABCC2), which is expressed on the bile canalicular membrane, is involved in the formation of bile acid-independent bile flow, and its hereditary defect results in the development of Dubin-Johnson syndrome in humans. Cholestasis is also induced by many acquired factors. As the mechanism for the acquired cholestasis, it is possible for us to assume that MRP2/ABCC2 is internalized by certain kinds of pathogenic stimuli. In the present study, we have demonstrated that MRP2/ABCC2 is internalized under pathological conditions, and proposed that such an internalization of efflux transporter may be related to the pathogenesis of cholestasis. We have also analyzed the localization and function of the SNPs forms of MRP2 molecules, and suggested that some kinds of mutation, which are not directly associated with the reduced function of MRP2/ABCC2 molecules per se, may be associated with the altered intracellular localization, and therefore, with the reduced in vivo function compared with the wild type transporter. In addition, it has been demonstrated that MRP3/ABCC3 is induced on the basolateral membrane under pathological conditions, in order to compensate for the reduced function of MRP2/ABCC2. Since the extent of the stage of cholestasisd may be affected by the function of MRP3/ABCC3, we have examined the function of human MRP3/ABCC3. It was demonstrated that MRP3/ABCC3 accepts MRP2/ABCC2 substrates, along with the monovalent bile salts which are the selective substrates for the bile salt export pump (BSEP/ABCB11). Together with our findings with the perfused liver, we could identify MRP3/ABCC3 as the membrane protein which may be involved in the rescue of hepatocytes under pathological conditions. It was also suggested that the extent of MRP3/ABCC3 induction may affect the severitv of the cholestasis.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Shoda J et al.: "The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliary secretory function"Am J Gastroenterol. 96. 3368-3378 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Asamoto Y et al.: "Bile-salt hydrophobicity is a key factor regulating rat liver plasma-membrane communication : relation to bilayer structure, fluidity and transporter expression and function"Biochem J. 359. 605-610 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shoda J et al.: "Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi"Hepatology. 33. 1194-1205 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akita H et al.: "Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver"Pharm Res. 18. 1119-1125 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ji B et al.: "Multidrug resistance-associated protein 2 (MRP2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal"Free Radic Biol Med. 33. 370-378 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akita H et al.: "Sinusoidal efflux of taurocholate correlates with the hepatic expression level of Mrp3"Biochem Biophys Res Commun. 299. 681-687 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki H, Sugiyama Y: "Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2) : Its impact on drug disposition"Advanced Drug Delivery Reviews. 54. 1311-1331 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Xiong H et al.: "Mechanisms of Impaired Biliary Excretion of Acetaminophen Glucuronide after Acute Phenobarbital Treatment or Phenobarbital Pretreatment"Drug Metab Dispos. 30. 962-969 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shoda, J., Kano, M., Oda, K., Kamiya, J., Nimura, Y., Suzuki, H., Sugiyama, Y., Miyazaki, H., Todoroki, T., Stengelin, S., Kramer, W., Matsuzaki, Y., and Tanaka, N.: "The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliary secretory function"Am.J.Gastroenterol.. 96. 3368-3378 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Asamoto, Y, Tazuma, S., Ochi, H., Chayama, K., and Suzuki, H.: "Bile-salt hydrophobicity is a key factor regulating rat liver plasma-membrane communication : relation to bilayer structure, fluidity and transporter expression and function"Biochem. J.. 359. 605-610 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shoda, J., Oda, K., Suzuki, H., Sugiyama, Y., Ito, K., Cohen, D.E., Feng, L., Kamiya, J., Nimura, Y, Miyazaki, H., Kano, M., Matsuzaki, Y., and Tanaka, N.: "Etiologic significance of defects in cholesterol, phospbolipid, and bile acid metabolism in the liver of patients with intrahepatic calculi"Hepatology. 33. 1194-1205 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akita, H., Suzuki, H., and Sugiyama, Y.: "Sinusoidal efflux of taurocholate is enhanced in Mrp2-deficient rat liver"Pharm. Res.. 18. 1119-1125 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ji, B., Ito, K., Suzuki, H., Sugiyama, Y., and Horie, T.: "Multidrug resistance-associated protein 2 (MRP2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal"Free Radic.BioI.Med.. 33. 370-378 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akita, H., Suzuki, H., and Sugiyama, Y.: "Sinusoidal Efflux of Taurocholate Correlates with the Hepatic Expression Level of Mrp3"Biocbem.Biophys.Res.Commun.. 299. 681-687 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Suzuki, H., and Sugiyama, Y.: "Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2) : Its impact on drug disposition"Adv.Drug Deliv.. 54. 1311-1331 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Xiong, H., Suzuki, H., Sugiyama, Y., Meier, P.J., Pollack, G.M., and Brouwer, K.L.: "Mechanisms of impaired biliary excretion of acetaminophen glucuronide after acute phenobarbital treatment or phenobarbital pretreatment"Drug Metab.Dispos.. 962-969 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Akita H et al.: "Sinusoidal Efflux of Taurocholate Correlates with the Hepatic Expression Level of Mrp3"Biochem Biophys Res Commun. 299. 681-687 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suzuki H, Sugiyama Y: "Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2) : Its impact on drug disposition"Adv Drug Deliv Rev. 54. 1311-1331 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Xiong H et al.: "Mechanisms of impaired biliary, excretion of acetaminophen glucuronide after acute phenobarbital treatment or phenobarbital pretreatment"Drug Metab Dispos. 30. 962-969 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ji B et al.: "Multidrug resistance-associated protein 2 (MRP2) plays an important role in the biliary excretion of glutathione conjugates of 4-hydroxynonenal"Free Radic Biol Med. 33. 370-378 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Akita, et al.: "Transport activity of human MRP3 expressed in Sf9 cells : Comparative studies with rat MRP3"Pharm.Res.. 19. 34-41 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] J.Shoda, et al.: "The expression levels of plasma membrane transporters in the cholestatic liver of patients undergoing biliary drainage and their association with the impairment of biliar secretory function"Am.J.Gastroenterol.. 96. 3368-3378 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Y.Asamoto, et al.: "Bile-salt hydrophobicity is a key factor regulating rat liver plasma-membrane communication : relatio to bilayer structure, fluidity and transporter expression and function"Biochem.J.. 359. 605-610 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] J.Shoda, et al.: "Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi"Hepatology.. 33. 1194-1205 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Akita, et al.: "Efflux of taurocholate is enhanced in Mrp2-deficient rat liver"Pharm.Res.. 18. 1119-1125 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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