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Induction of CAR and the nuclear localization are promoted in HepG2 hepatoma cells arrested at G_1 phase of cell cycle : Association with gene expression of UGT1A1 and Gadd45β

Research Project

Project/Area Number 16590056
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionUniversity of Shizuoka

Principal Investigator

SUGATANI Junko  University of Shizuoka, School of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (30098131)

Co-Investigator(Kenkyū-buntansha) YOSHINARI Kouichi  University of Shizuoka, School of Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師 (60343399)
MIWA Masao  University of Shizuoka, School of Pharmaceutics Sciences, Professor, 薬学部, 教授 (10046287)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
KeywordsNuclear receptor / CAR / Cell cycle / Drug-metabolizing enzyme / UGT1A1 / Transcriptional cofactor / Growth factor / constitutive androstane receptor(CAR) / グルクロン酸抱合酵素UGT / A1 / コファクター / CYP2B6 / グルクロン酸抱合酵素
Research Abstract

UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates endogenous metabolites, such as bilirubin, and exogenous substances, and plays a critical role in their detoxification and excretion. We found the phenobarbital response activity to a 290-bp distal enhancer sequence (-3499/-3210) of the human UGT1A1 gene that is activated by the constitutive androstane receptor (CAR). In addition, we show that dexamethasone at submicromolar concentrations enhances the pregnane X receptor (PXR) activator-mediated expression of the UGT1A1 gene and protein in HepG2 cells. We investigated the molecular mechanism of UGT1A1 induction by glucocorticoids at submicromolar concentrations and PXR activators and the functional cross-talk between the glucocorticoid receptor (GR) and CAR/PXR. The glucocorticoid-response element (GRE) was characterized by cotransfection experiments, site-directed mutagenesis and electrophoretic mobility shift assays. Analysis of the human UGT1A1 promoter revealed GREs at -3404/-338 … More 9 and -3251/-3236 close to the CAR/PXR response element gtNR1 (-3382/-3367). Furthermore, in an in vitro reporter gene assay, dexamethasone effectively enhanced CAR/PXR-mediated transactivation of the 290-bp distal enhancer module in HepG2 cells and CV-1 cells in the presence of exogenously expressed GR and glucocorticoid receptor-interacting protein 1 (GRIP1). Taken together, these results demonstrate a rational mechanistic basis for UGT1A1 induction by glucocorticoids and PXR activators, showing that activated GR enhances CAR/PXR-mediated UGT1A1 regulation with the transcriptional cofactor GRIP1.
In this study, we demonstrate that induction of CAR and the nuclear localization are promoted in HepG2 hepatoma cells arrested at G_1 phase of cell cycle. Addition of epidermal growth factor to the cells decreased the expression of CAR. Moreover inhibition of CAR expression by RNA interference suppressed gene expression of UGT1A1 and Gadd45β. CAR may exert the effects by influencing the expression of gene involved in not only the metabolism of endogenous and exogenous substances but also the control of cell proliferation. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (32 results)

All 2006 2005 2004 Other

All Journal Article (28 results) Book (4 results)

  • [Journal Article] Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet.2006

    • Author(s)
      Kouichi Yoshinari, et al.
    • Journal Title

      Pharmaceut.Res.

    • NAID

      130004639309

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants.2006

    • Author(s)
      Kouichi Yoshinari, et al.
    • Journal Title

      Drug Metab.Dispos.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet.2006

    • Author(s)
      Kouichi Yoshinari, Shunsuke Takagi, Teruyasu Yoshimasa, Junko Sugatani, Masao Miwa
    • Journal Title

      Pharmaceut.Res. DOI : 10. 1007/sl 1095-006-0071-6

    • NAID

      130004639309

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants.2006

    • Author(s)
      Kouichi Yoshinari, Nao Okino, Takeshi Sato, Junko Sugatani, Masao Miwa
    • Journal Title

      Drug Metab. Dispos. DOI : 10.1124/dmd

      Volume: 34 Issue: 7 Pages: 1081-1089

    • DOI

      10.1124/dmd.105.007286

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease.2005

    • Author(s)
      Takaomi Minami, et al.
    • Journal Title

      J.Pediatr. 147(1)

      Pages: 78-83

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Physico-chemical characterization and biological effects of inulin enzymatically synthesized from sucrose.2005

    • Author(s)
      Tadashi Wada, et al.
    • Journal Title

      J.Agric.Food.Chem. 53

      Pages: 1246-1253

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of human UGT1A1 gene expression : Activated GR enhances CAR/PXR-mediated UGT1A1 regulation with GRIP1.2005

    • Author(s)
      Junko Sugatani et al.
    • Journal Title

      Mol.Pharmacol 67(3)

      Pages: 845-855

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulation of the human UGT1A1 gene by nuclear receptors CAR, PXR and GR. In "Conjugation Enzymes".2005

    • Author(s)
      J.Sugatani, T.Sueyoshi, M.Negishi, M.Miwa
    • Journal Title

      Methods in Enzymology (H.Sies, L.Packer, eds.) Elsevier Inc

      Pages: 92-104

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease.2005

    • Author(s)
      Takaomi Minami, Hiroyuki Suzuki, Takashi Takeuchi, Shigeru Uemura, Junko Sugatani, Norishige Yoshikawa
    • Journal Title

      J.Pediatr. 147(1)

      Pages: 78-83

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Physico-chemical characterization and biological effects of inulin enzymatically synthesized from sucrose.2005

    • Author(s)
      Tadashi Wada, Junko Sugatani, Etsuko Terada, Masao Ohguchi, Masao Miwa
    • Journal Title

      J.Agric.Food.Chem. 53

      Pages: 1246-1253

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of human UGT1A1 gene expression : Activated GR enhances CAR/PXR-mediated UGT1A1 regulation with GRIP1.2005

    • Author(s)
      Junko Sugatani, Shinichi Nishitani, Kasumi Yamakawa, Kouichi Yoshinari, Tatsuya Sueyoshi, Masahiko Negishi, Masao Miwa
    • Journal Title

      Mol.Pharmacol. 67(3)

      Pages: 845-855

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Transcriptional regulation of human UGT1A1 gene expression: Activated GR enhances CAR/PXR-mediated UGT1A1 regulation with GRIP1.2005

    • Author(s)
      Junko Sugatani et al.
    • Journal Title

      Mol.Pharlnacol. 67(3)

      Pages: 845-855

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Physico-chemical characterization and biological effects of inulin enzymatically synthesized from sucrose.2005

    • Author(s)
      Tadashi Wada et al.
    • Journal Title

      J.Agric.Food Chem. 53(4)

      Pages: 1246-1253

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease.2005

    • Author(s)
      Takaomi Minami et al.
    • Journal Title

      J.Pediatr. 147(1)

      Pages: 78-83

    • Related Report
      2005 Annual Research Report
  • [Journal Article] A polymorphism in plasma platelet-activating factor acetylhydrolase is involved in resistance to immunoglobulin treatment in Kawasaki disease.2005

    • Author(s)
      Takaomi Minami et al.
    • Journal Title

      J.Pediatr. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Physico-chemical characterization and biological effects of inulin enzymatically synthesized from sucrose.2005

    • Author(s)
      Tadashi Wada et al.
    • Journal Title

      J.Agric.Food Chem. 53・4

      Pages: 1246-1253

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transcriptional regulation of human UGT1A1 gene expression : Activated GR enhances CAR/PXR-mediated UGT1A1 regulation with GRIP1.2005

    • Author(s)
      Junko Sugatani et al.
    • Journal Title

      Mol.Pharmacol. 67・3

      Pages: 845-855

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression and Induction of Cytochromes P450 in Rat White Adipose Tissue.2004

    • Author(s)
      Kouichi Yoshinari, et al.
    • Journal Title

      J.Pharmacol.Exp Ther. 311

      Pages: 147-154

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tea polyphenols inhibit acetyl-CoA:1-alkyl-sn-glycero-3- phosphocholine acetyltransferase (a key enzyme in PAF biosynthesis) and PAF- induced platelet aggregation.2004

    • Author(s)
      Junko Sugatani, et al.
    • Journal Title

      Intern.Arch.Allergy Immunol. 134

      Pages: 17-28

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The induction of human bilirubin UDP-glucuronosyltransferase mediated through a distal enhancer module by flavonoids and xenobiotics.2004

    • Author(s)
      Junko Sugatani, et al.
    • Journal Title

      Biochem.Phalmacol. 67(5)

      Pages: 989-1000

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression and Induction of Cytochromes P450 in Rat White Adipose Tissue.2004

    • Author(s)
      Kouichi Yoshinari, Takeshi Sato, Nao Okino, Junko Sugatani, Masao Miwa
    • Journal Title

      J.Pharmacol.Exp Ther. 311

      Pages: 147-154

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tea polyphenols inhibit acetyl-CoA : l-alkyl-sn-glycero-3- phosphocholine acetyltransferase (a key enzyme in PAF biosynthesis) and PAF- induced platelet aggregation.2004

    • Author(s)
      Junko Sugatani, Nana Fukazawa, Kenji Ujihara, Kouichi Yoshinari, Ikuo Abe, Hiroshi Noguchi, Masao Miwa
    • Journal Title

      Intern.Arch.Allergy Immunol. 134

      Pages: 17-28

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The induction of human bilirubin UDP-glucuronosyltransferase mediated through a distal enhancer module by flavonoids and xenobiotics.2004

    • Author(s)
      Junko Sugatani, Kasumi Yamakawa, Eri Tonda, Shinichi Nishitani, Kouichi Yoshinari, Masakuni Degawa, Ikuro Abe, Hiroshi Noguchi, Masao Miwa
    • Journal Title

      Biochem. Phalmacol. 67(5)

      Pages: 989-1000

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression and induction of cytochromes P450 in rat white adipose tissue.2004

    • Author(s)
      Kouichi Yoshinari et al.
    • Journal Title

      J.Pharmacol.Exp.Ther. 311・1

      Pages: 147-154

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Tea polyphenols inhibit acetyl-CoA : 1-alkyl-sn-glycero-3-phosphocholine acetyltransferase (a key enzyme in PAF biosynthesis) and PAF-induced platelet aggregation.2004

    • Author(s)
      Junko Sugatani et al.
    • Journal Title

      Intern.Arch.Allergy Immunol. 134

      Pages: 17-28

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The induction of human bilirubin UDP-glucuronosyltransferase mediated through a distal enhancer module by flavonoids and xenobiotics.2004

    • Author(s)
      Junko Sugatani et al.
    • Journal Title

      Biochem.Pharmacol. 67・5

      Pages: 989-1000

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants.

    • Author(s)
      Kouichi Yoshinari et al.
    • Journal Title

      Drug Metab.Dispos., (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Hepatic CYP3A expression is attenuated in obese mice fed a high-fat diet,

    • Author(s)
      Kouichi Yoshinari et al.
    • Journal Title

      Pharmaceut.Res., (in press)

    • NAID

      130004639309

    • Related Report
      2005 Annual Research Report
  • [Book] 茶の効能と応用開発 Health beneficial functions and development of tea goods - 血小板凝集抑制.2006

    • Author(s)
      菅谷純子, 三輪匡男
    • Total Pages
      9
    • Publisher
      シーエムシー出版
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 茶の効能と応用開発Health beneficial functions and development of tea goods2006

    • Author(s)
      菅谷 純子 他
    • Publisher
      シーエムシー出版(監修:伊勢村護)
    • Related Report
      2005 Annual Research Report
  • [Book] Regulation of the human UGT1A1 gene by nuclear receptors CAR, PXR and GR. In "Conjugation Enzymes".2005

    • Author(s)
      Junko Sugatani, et al.
    • Total Pages
      13
    • Publisher
      Elsevier Inc.
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] In "Conjugation Enzymes".(H.Sies, and L.Packer, eds.) Methods in Enzymology.2005

    • Author(s)
      Junko Sugatani et al.
    • Publisher
      Elsevier Inc.
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2023-03-16  

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