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Investigation of the next-generation and late-onset effects of drugs focusing on liver maturation and liver function regulated by the nuclear receptors PXR and CAR

Research Project

Project/Area Number 20K07202
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47060:Clinical pharmacy-related
Research InstitutionUniversity of Shizuoka

Principal Investigator

Yoshinari Kouichi  静岡県立大学, 薬学部, 教授 (60343399)

Co-Investigator(Kenkyū-buntansha) 志津 怜太  静岡県立大学, 薬学部, 助教 (50803912)
保坂 卓臣  静岡県立大学, 薬学部, 助教 (30611579)
柿崎 暁  群馬大学, 大学院医学系研究科, 講師 (80344935)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords核内受容体 / 化学物質 / 肝臓 / 甲状腺ホルモン / 薬物代謝酵素 / 成長障害 / 遺伝子発現 / CAR / 新生仔 / 発達毒性 / 次世代影響
Outline of Research at the Start

化学物質がヒトの出生や発育に影響を及ぼすことが示されつつある。また、申請者らは化学物質が生体内化学物質センサーであるPXR及びCARを介して肝臓の機能や再生に影響を及ぼすことを明らかにしている。そこで本研究では、胎児期や新生仔期の肝臓におけるPXR及びCARの活性化が、肝臓の発達や機能に及ぼす影響、さらにはその全身影響や疾患の発症に対する影響を解析する。これらにより、胎児期や乳幼児期における化学物質曝露が及ぼす新たな健康影響の解明を目指す。

Outline of Final Research Achievements

In this study, we investigated the effects of the nuclear receptor CAR activation on the development of infant mice. Intraperitoneal administration of a CAR activator to 15-day-old and 8-week-old male mice induced changes in the expression of endocrine metabolism-related genes in an infant-specific manner, including upregulation of thyroid hormone-metabolizing enzymes and down-regulation of target genes of thyroid hormone signaling. Next, a CAR activator was administered to 15-day-old wild-type and CAR-null male mice. We observed treatment-associated decreases in body weight gain and grip strength and increases in plasma TSH levels only in wild-type mice. These results suggest that CAR activation during infancy causes growth retardation associated with the suppression of thyroid hormone signaling.

Academic Significance and Societal Importance of the Research Achievements

近年、胎児期や乳幼児期における化学物質のばく露が発達や成長に及ぼす影響が社会的な問題となっている。肝に高発現する核内受容体CARは、多種多様な化学物質により活性化されて種々の代謝酵素の発現を誘導し、ホルモン代謝やエネルギー代謝にも影響を与える。そこで本研究では、CAR活性化が乳幼児期マウスの発達に及ぼす影響の解明を目指した。その結果、乳幼児期における化学物質曝露によるCARの活性化は、甲状腺ホルモンの代謝を亢進し、甲状腺ホルモンシグナルの抑制に伴う成長遅延を引き起こす可能性が示された。これらの結果は、化学物質の発生・発達毒性の分子機序を理解する上で有用な知見を提供すると考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (15 results)

All 2023 2022 2021 2020

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 3 results) Presentation (8 results) (of which Invited: 1 results)

  • [Journal Article] PPARα Induces the Expression of CAR That Works as a Negative Regulator of PPARα Functions in Mouse Livers2023

    • Author(s)
      Ryota Shizu, Yuta Otsuka, Chizuru Ishii, Kanako Ezaki, Kouichi Yoshinari
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 4 Pages: 3953-3953

    • DOI

      10.3390/ijms24043953

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Distinct Roles of the Sister Nuclear Receptors PXR and CAR in Liver Cancer Development2022

    • Author(s)
      Kouichi Yoshinari, Ryota Shizu
    • Journal Title

      Drug Metabolism and Disposition

      Volume: 50 Issue: 7 Pages: 1019-1026

    • DOI

      10.1124/dmd.121.000481

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PXR suppresses PPARα-dependent HMGCS2 gene transcription by inhibiting the interaction between PPARα and PGC1α2021

    • Author(s)
      R. Shizu, K. Ezaki, T. Sato, A. Sugawara, T. Hosaka, T. Sasaki, K. Yoshinari
    • Journal Title

      Cells

      Volume: 10 Issue: 12 Pages: 3550-3550

    • DOI

      10.3390/cells10123550

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The influence of the long‐term chemical activation of the nuclear receptor pregnane X receptor (PXR) on liver carcinogenesis in mice2021

    • Author(s)
      Ryota Shizu, Mai Ishimura, Sumihito Nobusawa, Takuomi Hosaka, Takamitsu Sasaki, Satoru Kakizaki, Kouichi Yoshinari
    • Journal Title

      Archives of Toxicology

      Volume: 95 Issue: 3 Pages: 1089-1102

    • DOI

      10.1007/s00204-020-02955-4

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] PXR functionally interacts with NF-κB and AP-1 to downregulate the inflammation-induced expression of chemokine CXCL2 in mice.2020

    • Author(s)
      Maya Okamura, Ryota Shizu, Taiki Abe, Susumu Kodama, Takuomi Hosaka, Takamitsu Sasaki, Kouichi Yoshinari
    • Journal Title

      Cells

      Volume: 9 Issue: 10 Pages: 2520-2520

    • DOI

      10.3390/cells9102296

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Antiepileptic Drug?Activated Constitutive Androstane Receptor Inhibits Peroxisome Proliferator?Activated Receptorαand Peroxisome Proliferator?Activated ReceptorγCoactivator 1α?Dependent Gene Expression to Increase Blood Triglyceride Levels2020

    • Author(s)
      Shizu Ryota、Otsuka Yuta、Ezaki Kanako、Ishii Chizuru、Arakawa Shingo、Amaike Yuto、Abe Taiki、Hosaka Takuomi、Sasaki Takamitsu、Kanno Yuichiro、Miyata Masaaki、Yamazoe Yasushi、Yoshinari Kouichi
    • Journal Title

      Molecular Pharmacology

      Volume: 98 Issue: 5 Pages: 634-647

    • DOI

      10.1124/molpharm.120.000103

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Nuclear receptor CAR-mediated liver cancer and its species differences2020

    • Author(s)
      Shizu Ryota、Yoshinari Kouichi
    • Journal Title

      Expert Opinion on Drug Metabolism & Toxicology

      Volume: 16 Issue: 4 Pages: 343-351

    • DOI

      10.1080/17425255.2020.1746268

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 乳幼児期における化学物質曝露はCAR活性化を介して成長遅延を引き起こす2022

    • Author(s)
      田代紗莉依、志津怜太、保坂卓臣、菅野裕一朗、吉成浩一
    • Organizer
      第68回日本薬学会東海支部総会・大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 化学物質曝露による核内受容体CAR活性化が乳幼児の発達に及ぼす影響2022

    • Author(s)
      田代紗莉依、志津怜太、保坂卓臣、菅野裕一朗、吉成浩一
    • Organizer
      第49回日本毒性学会学術年会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 乳幼児期マウスにおける核内受容体CARの活性化が甲状腺ホルモンシグナルに及ぼす影響2021

    • Author(s)
      田代紗莉依、志津怜太、保坂卓臣、菅野裕一朗、吉成浩一
    • Organizer
      第4回医薬品毒性機序研究会
    • Related Report
      2021 Research-status Report
  • [Presentation] 乳幼児期における核内受容体CAR活性化の甲状腺ホルモンシグナルに対する影響2021

    • Author(s)
      田代紗莉依、志津怜太、保坂卓臣、菅野裕一朗、吉成浩一
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会2021
    • Related Report
      2021 Research-status Report
  • [Presentation] 核内受容体PXRと肝細胞増殖・肝発がん2021

    • Author(s)
      吉成浩一
    • Organizer
      環境ホルモン学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] ラット反復投与毒性試験データベースを利用した小葉中心性肝細胞肥大の発現機序解析2021

    • Author(s)
      柴田尚輝、志津怜太、保坂卓臣、菅野裕一朗、吉成浩一
    • Organizer
      第38回日本毒性学会学術年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 化学物質によるPXR活性化のマウス肝発がんへの影響解析2020

    • Author(s)
      志津怜太、石村麻衣、信澤純人、保坂卓臣、佐々木崇光、柿崎暁、吉成浩一
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 抗てんかん薬によるCARの活性化はPPARαの抑制を介して血中脂質レベルを増加させる2020

    • Author(s)
      志津怜太、江崎香奈子、保坂卓臣、佐々木崇光、菅野裕一朗、吉成浩一
    • Organizer
      日本病院薬剤師会東海ブロック・日本薬学会東海支部合同学術大会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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