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Search for the new, endogenous compound with multidrug resistance modulating activity and its application to cancer chemotherapy

Research Project

Project/Area Number 11672169
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionHiroshima University

Principal Investigator

TAKANO Mikihisa  Hiroshima University, Faculty of Medicine, Professor, 医学部, 教授 (20211336)

Co-Investigator(Kenkyū-buntansha) NAGAI Junya  Hiroshima University, Faculty of Medicine, Instructor, 医学部, 助手 (20301301)
MURAKAMI Teruo  Hiroshima University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (20136055)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsP-glycoprotein / renal failure / hepatic failure / endogenous inhibitor / corticosterone / estrogen / multidrug resistance / endocrine disrupting chemical / ローダミン123 / 内因性物質
Research Abstract

P-Glycoprotein (P-gp) is a drug efflux pump and confers multidrug resistance to cancer cells. In order to reverse multidrug resistance, compounds having the inhibitory potency on P-gp is now actively searched. On one hand, P-gp in normal tissues is important as a determinant of drug handling in the body. In the present study, the function of P-gp under disease states was examined, and the involvement of endogenous P-gp inhibitors was shown. In addition, to find out the new multidrug resistance modulators, we attempted to identify the endogenous P-gp inhibitors.
In-vivo P-gp function was examined in acute renal or hepatic failure rats, by measuring the handling of rhodamine 123, a P-gp substrate, in various tissues. Interestingly, the function of P-gp was suppressed not only in target injury tissue but also in other tissues. The expression levels of P-gp in these tissues did not decrease, rather increased in injury tissue. In addition, the inhibitory potency of the plasma from disease rats on P-gp was stronger than that from normal rats, indicating the involvement of endogenous P-gp inhibitors. In fact, the plasma concentration of corticosterone, an endogenous P-gp-related compound, increased in disease rats. In volunteers with normal kidney function, endogenous P-gp inhibitors were found to be excreted into the urine, one of which was identified to be equilin, an estrogen. During the study, di-2-ethylhexyl phthalate (DEHP), which is assumed to be an endocrine disrupting chemicals (EDCs), was found in the urine, though DEHP itself did not have direct inhibitory effect on P-gp. Further studies on endogenous P-gp inhibitors would help to identify new and useful multidrug resistance modulators for cancer chemotherapy.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (7 results)

All Other

All Publications (7 results)

  • [Publications] Huang,Z.-H.: "Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure"Eur.J.Pharmacol.. 406. 453-460 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Huang,Z.-H.: "Expression and function of P-glycoprotein in rats with carbon tetrachloride-induced acute hepatic failure"J.Pharm.Pharmacol.. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Huang, Z.-H.: "Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure"Eur.J.Pharmacol.. 406. 453-460 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Huang, Z.-H.: "Expression and function of P-glycoprotein in rats with carbon tetrachloride-induced acute hepatic failure"J.Pharm.Pharmacol.. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Huang,Z.-H.: "Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure"Eur.J.Pharmacol.. 406. 453-460 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Huang,Z.-H.: "Expression and function of P-glycoprotein in rats with carbon tetrachloride-induced acute hepatic failure"J.Pharm.Pharmacol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kajikawa, T.: "Role of P-glycoprotein in ocular clearance of rhodamine 123 in rabbits"Pharm. Res.. (in press). (2000)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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