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Molecular mechanism of steroid transporter P-glycoprotein

Research Project

Project/Area Number 04660085
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field 応用生物化学・栄養化学
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

UEDA Kazumitsu  Kyoto University Faculty of Agriculture Assistant Professor, 農学部, 助手 (10151789)

Co-Investigator(Kenkyū-buntansha) HIRAI Midori  Kyoto University Faculty of Medicine Assistant Professor, 医学部, 助手 (70228766)
TANIGAWARA Tusuke  Kobe University Faculty of Medicine Associated Professor, 医学部, 講師 (30179832)
KIOKA Noriyuki  Kyoto University Faculty of Agriculture Assistant Professor, 農学部, 助手 (90234179)
KOMANO Tohru  Kyoto University Faculty of Agriculture Professor, 農学部, 教授 (30026413)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1992: ¥1,300,000 (Direct Cost: ¥1,300,000)
KeywordsP-glycoprotein / Multidrug resistance / Steroid hormone / MDR1 gene / Cancer / Transporter / Chemotherapy / トランスポーター / ジゴキシン
Research Abstract

P-glycoprotein acts as an energy-dependent efflux pump that exports anticancer agents out of the cell, lowering their intracellular concentration to sublethal levels, and is considered to be important in multidrug resistance (MDR) of human tumors. P-glycoprotein is expressed in several normal human tissues, but physiological substrates of P-glycoprotein have not been fully understood.
To analyze the mechanism of drug transport and physiological substrates, we established a transepithelial transport system. We expressed MDR1 cDNA isolated from human normal adrenal in LLC-PK1 cells, which are derived from porcine kidney proximal tubule. One transformant (LLC-GA5-COL300) showed 54-, 150-, and 167-fold resistance to colchicine, vinblastine, and adriamycin, respectively, compared to LLC-PK1 cells. LLC-PK_1 and the P-glycoprotein-expressing transfectant cells form a highly polarized epithelium, and electron microscopic immunocytochemistry using a monoclonal antibody MRK16 showed that human P- … More glycoprotein is specifically expressed on the apical surface of the transfectant cells.
By using this transepithelial transport system, we measured transport of ^3H-labeled aldosterone, corticosterone, cortisol, deoxycorticosterone, dexamethasone, estradiol, estriol, progesterone, testesterone. In the transfectant cells, basal to apical transport of aldosterone, cortisol, estriol and dexamethasone increased and their apical to basal transport decreased compared to those in the host cells. But transport of corticosterone, deoxycorticosterone, estradiol, progesterone, testesterone was indistinguishable in both cell lines. Transepithelial transport of aldosterone, cortisol, estriol and dexamethasone was inhibited by verapamil. These results indicate that human P-glycoprotein transports aldosterone, cortisol, estriol and dexamethasone.
Cortisol, a glucocorticoid, is the main steroid produced in the human adrenal. Aldosterone is the main mineralocorticoid produced in the human adrenal. Estriol is the main estrogen produced during pregnancy in the fetoplacental unit. P-glycoprotein is expressed in the human adrenal cortex and the pregnant uterus and placenta. These results suggest that human P-glycoprotein functions as a steroid transporter in the adrenal cortex and in the fetoplacental unit during pregnancy. Less

Report

(3 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Saeki,T.: "Human P-glycoprotein Transports cyclosporin A and FK506." J.Biol.Chem.268. 6077-6080 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Saeki,T.: "P-glycoprotein-mediated transcellular transport of MDR-reversing agents." FEBS Lett.324. 99-102 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ueda,K.: "Functional expression of human P-glycoprotein in Schizosaccharomyces pombe." FEBS Lett.330. 279-282 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Okamura,N.: "Digoxin-cyclosporin A interaction:Modulation of the multidrug transporter P-glycoprotein the kidney." J.Phamacol.Exp.Ther.266. 1614-1619 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ueda, K.: "Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone but not progesterone." J.Biol.Chem.267. 24248-24252 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Shimabuku, A.M.: "P-glycoprotein : ATP hydrolysis by the N-terminal nucleotide-binding domain." J.Biol.Chem.267. 4308-4311 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Tanigawara, Y.: "Transport of degoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1)." J.Phamacol.Exp.Ther.263. 840-845 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Chin, K.-V.: "Modulation of activity of the promoter of the human MDR1 gene by Ras and p53." Science. 255. 459-462 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kioka, N.: "Heat shock responsive elements in the induction of multidrug resistance gene (MDR1)." FEBS Lett.301. 37-40 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kioka, N.: "Quercetin, a bioflavonoid, inhibits the increase of human multidrug resistance gene (MDR1) expression caused by arsenite." FEBS Lett.301. 307-309 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Saeki, T.: "Specific drug binding by purified lipid-reconstituted P-glycoprotein : dependence on the lipid composition." Biochim.Biophys.Acta. 1107. 105-110 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sugawara, I.: "Primer-dependent amplification of mdr1 mRNA by polymerase chain reaction." Jpn.J.Cancer Res.83. 131-133 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Sugawara, I.: "Preparation and characterization of a murine monoclonal antibody (MDR3M) reactive with mdr3 gene product." Jpn.J.Cancer Res.83. 795-797 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Saeki, T.: "Human P-glycoprotein Transports cyclosporin A and FK506." J.Biol.Chem.268. 6077-6080 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Saeki, T.: "P-glycoprotein-mediated transcellular transport of MDR-reversing agents." FEBS Lett.324. 99-102 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Ueda, K.: "Functional expression of human P-glycoprotein in chizosaccharomyces pombe." FEBS Lett.330. 279-282 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Okamura, N.: "Digoxin-cyclosporin A interaction : Modulation of the multidrug transporter P-glycoprotein the kidney." J.Phamacol.Exp.Ther.66. 1614-1619 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Saeki,T.: "Human P-glycoprotein Transports cyclosporin A and FK506." J.Biol.Chem.268. 6077-6080 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Saeki,T.: "P-glycoprotein-mediated transcellular transport of MDR-reversing agents." FEBS Lett.324. 99-102 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Ueda,K.: "Functional expression of human P-glycoprotein in Schizosaccharomyces pombe." FEBS Lett.330. 279-282 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okamura,N.: "Digoxin-cyclosporin A interaction:Modulation of the multidrug transporter P-glycoprotein the kidney." J.Phamacol.Exp.Ther.266. 1614-1619 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Saeki,T.: "Human P-glycoprotein Transports cyclosporin A and FK506" J.Biol.Chem.

    • Related Report
      1992 Annual Research Report
  • [Publications] Ueda,K.: "Human P-glycoprotein transports cortisol,aldosterone,and dexamethasone but not progesterone" J.Biol.Chem.267. 24248-24252 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Shimabuku,A.M.: "P-glycoprotein:ATP hydrolysis by the N-termimal nucleotide-binding domain" J.Biol.Chem. 267. 4308-4311 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Chin,K.-V.: "Modulation of activity of the promoter of the human MDR1 gene by Ras and p53" Science. 255. 459-462 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Tanigawara,Y.: "Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1)" J.Phamacol.Exp.Ther.263. 840-845 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kioka,N.: "Heat shock responsive elements in the induction of multidrug resistance gene(MDR1)" FFBS Lett.301. 37-40 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kioka,N.: "Quercetin,a bioflavonoid,inhibits the increse of human multidrug resistance gene(MDR1)expression caused by arsenite" FEBS Lett.301. 307-309 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Saeki,T.: "Specific drug binding by purified lipid-reconstituted P-glycoprotein:dependence on the lipid composition" Biochim.Biophys.Acta. 1107. 105-110 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sugawara,I.: "Primer-dependent amplification of mdrl mRNA by polymerase chain reaction" Jpn.J.Cancer Res.83. 131-133 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Sugawara,I.: "Preparation and characterization of a murine monoclonal antibody (MDR3M) reactive with mdr3 gene product" Jpn.J.Cancer Res.83. 795-797 (1992)

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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