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Exploration of the mechanism by which regulate hepatocyte specific functions and development of high functional hepatocyte culture system.

Research Project

Project/Area Number 25460088
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionNational Center for Child Health and Development

Principal Investigator

Nakamura Kazuaki  国立研究開発法人国立成育医療研究センター, 薬剤治療研究部, 室長 (80392356)

Research Collaborator Kyaw Htet Aung  
AIZAWA Kazuko  
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2013: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywords肝細胞培養系 / DNAメチル化 / 高機能培養肝細胞 / PKR / 転写因子
Outline of Final Research Achievements

In this study, we explored the mechanism by which regulate hepatocyte specific functions and developed high functional hepatocyte culture system. We found that inhibitor of DNA methyltransferase, zebularine, upregulates the expression of CYP genes in HepG2 cells through inhibiting DNA methyltransferase 1 (DNMT1) and double-stranded RNA dependent protein kinase (PKR). Whereas inhibition of either DNMT1 or PKR slightly upregulates CYP gene expression, combined inhibition of both DNMT1 and PKR markedly upregulates CYP gene expression. Furthermore, HepG2 cells treated with zebularine were more sensitive than control HepG2 cells to drug toxicity. Taken together, our results show that combined inhibition of DNMT1 and PKR in HepG2 cells leads to effective upregulation of expression of CYP genes, which is a novel mechanism, and also suggest that HepG2 cells treated with zebularine and thus having upregulated CYP gene expression may be useful for evaluating drug toxicity in vitro.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (14 results)

All 2016 2015 2014 2013 Other

All Journal Article (3 results) (of which Peer Reviewed: 3 results,  Open Access: 2 results,  Acknowledgement Compliant: 1 results) Presentation (9 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Remarks (2 results)

  • [Journal Article] DNA methyltransferase inhibitor zebularine induces human cholangiocarcinoma cell death through alteration of DNA methylation status.2015

    • Author(s)
      Nakamura K, Nakabayashi K, Kyaw Htet Aung, Aizawa K, Hori N, Yamauchi J, Hata K, Tanoue A.
    • Journal Title

      PLoS ONE

      Volume: 10 Issue: 3 Pages: e0120545-e0120545

    • DOI

      10.1371/journal.pone.0120545

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] contributed equally to this work. Hepatocytes buried in the cirrhotic livers of biliary atresia patients proliferate and function in the liver of uPA-NOG mice2014

    • Author(s)
      Suemizu H, Nakamura K, Kawai K, Higuchi Y, Kasahara M, Fujimoto J, Tanoue A, Nakamura M
    • Journal Title

      Liver Transplantation

      Volume: (In press) Issue: 9 Pages: 1127-1137

    • DOI

      10.1002/lt.23916

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatocyte transplantation using the living donor reduced-graft in a baby with ornithine transcarbamylase deficiency : a novel source for hepatocytes2014

    • Author(s)
      Enosawa S, Horikawa R, Yamamoto A, Sakamoto S, Shigeta T, Nosaka S, Fujimoto J, Tanoue A, Nakamura K, Umezawa A, Matsubara Y, Matsui A, Kasahara M
    • Journal Title

      Liver Transplantation

      Volume: 20 Issue: 3 Pages: 391-393

    • DOI

      10.1002/lt.23800

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] Regulation of Cell Death and Cell Specific Functions by Inhibition of DNA Methylation2016

    • Author(s)
      Kazuaki Nakamura
    • Organizer
      The 2016 World Congress on In Vitro Biology
    • Place of Presentation
      The Sheraton San Diego Hotel & Marina
    • Year and Date
      2016-06-11
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 高機能肝細胞培養系の検討と毒性評価系開発の試み2016

    • Author(s)
      中村和昭
    • Organizer
      日本組織培養学会第89回大会
    • Place of Presentation
      千里ライフサイエンスセンター
    • Year and Date
      2016-05-25
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] DNAメチル化阻害剤ゼブラリンによるHepG2細胞のシトクロムP450遺伝子発現亢進2015

    • Author(s)
      中村和昭、相澤和子、Kyaw Htet Aung, 田上昭人
    • Organizer
      第42回日本毒性学会学術年会
    • Place of Presentation
      石川県立音楽堂
    • Year and Date
      2015-06-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] DNAメチル化阻害剤ゼブラリンの抗胆管癌作用の検討2015

    • Author(s)
      中村和昭、中林一彦、相澤和子、Kyaw Htet Aung、秦健一郎、田上昭人
    • Organizer
      日本組織培養学会第88回大会
    • Place of Presentation
      広島大学歯学部
    • Year and Date
      2015-05-26
    • Related Report
      2015 Annual Research Report
  • [Presentation] DNAメチル化阻害剤ゼブラリンのヒト胆管癌細胞に対する抗腫瘍活性2014

    • Author(s)
      中村和昭、中林一彦、Kyaw Htet Aung、秦健一郎、田上昭人
    • Organizer
      日本分子生物学会
    • Place of Presentation
      パシフィコ横浜
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Research-status Report
  • [Presentation] Zebularine enhances expression of cytochrome P450 genes and induces cell death in HepG2 cells2014

    • Author(s)
      Nakamura K, Aizawa K, Nakabayashi K, Hori N, Kyaw Htet Anung, Hata K, Tanoue A
    • Organizer
      Japanese Tissue Culture Association
    • Place of Presentation
      星陵会館
    • Year and Date
      2014-05-29 – 2014-05-30
    • Related Report
      2014 Research-status Report
  • [Presentation] DNAメチル化阻害剤ゼブラリンによるHepG2細胞の肝機能亢進と細胞死誘導2014

    • Author(s)
      中村和昭, 相澤和子, 中林一彦, 堀尚子, Kyaw Htet Anung, 秦健一郎, 田上昭人
    • Organizer
      日本組織培養学会
    • Place of Presentation
      星陵会館
    • Related Report
      2013 Research-status Report
  • [Presentation] DNAメチル化阻害剤ゼブラリンのヒト肝細胞癌に対する抗腫瘍活性2013

    • Author(s)
      中村和昭、中林一彦、秦健一郎、田上昭人
    • Organizer
      日本分子生物学会
    • Place of Presentation
      神戸国際展示場
    • Related Report
      2013 Research-status Report
  • [Presentation] DNAメチル化阻害剤ゼブラリンによるヒト肝細胞癌に対する細胞毒性2013

    • Author(s)
      中村和昭、中林一彦、秦健一郎、田上昭人
    • Organizer
      日本毒性学会
    • Place of Presentation
      幕張メッセ
    • Related Report
      2013 Research-status Report
  • [Remarks] 国立成育医療研究センター研究所薬剤治療研究部ホームページ

    • URL

      http://www.ncchd.go.jp/scholar/research/section/pharmac/index.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 国立成育医療研究センター研究所薬剤治療研究部ホームページ

    • URL

      http://nrichd.ncchd.go.jp/pharmac/index.html

    • Related Report
      2014 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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