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Mechanism of intestinal induction of P-glycoprotein

Research Project

Project/Area Number 20590139
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionChiba University

Principal Investigator

KOBAYASHI Kaoru  Chiba University, 大学院・薬学研究院, 准教授 (30255864)

Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2008: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsP-糖タンパク質 / 誘導 / 転写調節 / 核内レセプター / トランスポーター
Research Abstract

Induction of intestinal P-glycoprotein (gene name, MDR1) by rifampicin (RIF) is mediated by transcriptional activation of MDR1 gene by pregnane X receptor (PXR). In this study, we found that endogenous MDR1 mRNA was highly induced by RIF in colon carcinoma cell line (LS180) but not in hepatocarcinoma cell line (HepG2), although PXR is expressed in both cell lines. In addition, we identified cis- and trans-regulatory factors responsible for the intestine-specific induction of MDR1 gene by using these cell lines. Reporter activities of a distal regulatory cluster (-7970/-7011) were markedly increased by RIF in only LS180 cells. The reporter activities in LS180 cells were decreased to the level observed in HepG2 cells by deletion or mutation of the DR4 motifs in the distal regulatory cluster. Moreover, we cloned epithelial-specific ets factor (ESE-3) that was highly expressed in LS180 cells but not in HepG2 cells. Exogenous expression of ESE-3 into HepG2 cells resulted in the transcriptional activation of MDR1 gene by RIF. The reporter activities enhanced by ESE-3 were completely decreased by mutation of the DR4 motifs. A knock-down of ESE-3 by siRNA significantly attenuated the induction of endogenous MDR1 mRNA by RIF in LS180 cells. These results suggest that ESE-3 is a novel trans-regulatory factor responsible for the intestinal induction of MDR1 gene by RIF via the DR4 motifs of MDR1 gene. Moreover, there was a significant correlation between the induction of mRNA and reporter activity for MDR1 by 21 different compounds. Therefore, the induction of mRNA and reporter activity for MDR1 by test compounds in LS180 cells will be possible to predict an intestinal induction of P-glycoprotein.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (7 results)

All 2010 2009 2008 Other

All Presentation (5 results) Remarks (2 results)

  • [Presentation] A novel mechanism of intestinal induction of MDR1 gene by rifampicin2010

    • Author(s)
      小林カオル, 6名
    • Organizer
      日本薬物動態学会第25回年会
    • Place of Presentation
      大宮ソニックシティ
    • Year and Date
      2010-10-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] MDR1遺伝子の小腸特異的誘導に関する新規メカニズム2010

    • Author(s)
      小林カオル、亀山直哉、清水晶子、山崎由貴、遠藤美佳、降幡知巳、千葉寛
    • Organizer
      第25回日本薬物動態学会年会
    • Place of Presentation
      大宮
    • Related Report
      2010 Final Research Report
  • [Presentation] PXRを介したヒトMDR1の腸管特異的誘導に関する研究2009

    • Author(s)
      亀山直哉、清水晶子、山崎由貴、小林カオル、千葉寛
    • Organizer
      第24回日本薬物動態学会年会
    • Place of Presentation
      京都
    • Related Report
      2010 Final Research Report 2009 Annual Research Report
  • [Presentation] MDRIおよびCYP3A4遺伝子の誘導に関するmRNA発現量とレポーター活性の相関2009

    • Author(s)
      清水晶子, 亀山直哉, 小林カオル, 千葉寛
    • Organizer
      日本薬学会第129年会
    • Place of Presentation
      京都
    • Related Report
      2010 Final Research Report
  • [Presentation] ヒト腸管に発現するMDRl遺伝子のリファンピシンによる転写活性化におけるproximalプロモーターの重要性2008

    • Author(s)
      清水晶子、亀山直哉、小林カオル、千葉寛
    • Organizer
      第23回日本薬物動態学会年会
    • Place of Presentation
      熊本市
    • Year and Date
      2008-10-31
    • Related Report
      2008 Annual Research Report
  • [Remarks] ホームページ等

    • URL

      http://www.p.chiba-u.ac.jp/lab/yakubutu/framepage4.html

    • Related Report
      2010 Final Research Report
  • [Remarks]

    • URL

      http://www.p.chiba-u.ac.jp/lab/yakubutu/framepage4.html

    • Related Report
      2010 Annual Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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