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Analysis of idiosyncratic drug toxicity using mitochondria isolated from an animal model of metabolic syndrome

Research Project

Project/Area Number 26670084
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Medical pharmacy
Research InstitutionTeikyo Heisei University

Principal Investigator

HORIE Toshiharu  帝京平成大学, 薬学部, 教授 (90120154)

Co-Investigator(Kenkyū-buntansha) HAMADA Kazuma  帝京平成大学, 薬学部, 講師 (90596884)
NAKANO Takafumi  帝京平成大学, 薬学部, 助教 (40720793)
Project Period (FY) 2014-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords肝障害 / 生活習慣病 / ミトコンドリア毒性 / 医薬品 / 毒性予測 / ミトコンドリア / 医薬品毒性 / MPT / 酸素消費 / 糖尿病 / 薬物感受性 / 特異体質性薬物毒性
Outline of Final Research Achievements

Although it has been suggested that underlying disease could be a nongenetic risk factor for idiosyncratic drug-induced liver injury (DILI), little is known about the mechanisms that determine the increased sensitivity to DILI. In addition to patient risk factors, drug related risk factors including mitochondrial toxicity have also been proposed to explain the complex mechanisms of DILI. The objective of this study was to determine whether the fatty liver in type 2 diabetes (T2D) is more susceptible to mitochondrial permeability transition (MPT), characterized by swelling and membrane depolarization that are associated with DILI. Our result showed that T2D enhanced susceptibility to drug-induced MPT. We also demonstrated that the liver mitochondria isolated from T2D mice had increased oxygen consumption stimulated by an uncoupler compared to normal liver mitochondria (NLM). It might be a useful tool to predict DILI in T2D patients, because its sensitivity to drug is different from NLM.

Report

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

    (11 results)

All 2016 2015 Other

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 5 results,  Acknowledgement Compliant: 3 results) Presentation (5 results) Remarks (1 results)

  • [Journal Article] Pharmacokinetic Herb-Drug Interactions: Insight into Mechanisms and Consequences.2016

    • Author(s)
      Oga EF, Sekine S, Shitara Y, Horie T.
    • Journal Title

      Eur J Drug Metab Pharmacokinet.

      Volume: 41 Issue: 2 Pages: 93-108

    • DOI

      10.1007/s13318-015-0296-z

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Establishment of a drug-induced, bile acid-dependent hepatotoxicity model using HepaRG cells2016

    • Author(s)
      Susukida T, Sekine S, Nozaki M, Tokizono M, Oizumi K, Horie T, Ito K
    • Journal Title

      J Pharm Sci

      Volume: 43 Issue: 4 Pages: 1550-1560

    • DOI

      10.1016/j.xphs.2016.01.013

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Basal efflux of bile acids contributes to drug-induced bile acid-dependent hepatocyte toxicity in rat sandwich-cultured hepatocytes.2015

    • Author(s)
      Susukida T, Sekine S, Ogimura E, Aoki S, Oizumi K, Horie T, Ito K.
    • Journal Title

      Toxicol In Vitro

      Volume: 29 Issue: 7 Pages: 1454-1463

    • DOI

      10.1016/j.tiv.2015.06.004

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition.2015

    • Author(s)
      Shirakawa M, Sekine S, Tanaka A, Horie T, Ito K.
    • Journal Title

      Toxicol Appl Pharmacol

      Volume: 288 Issue: 1 Pages: 12-18

    • DOI

      10.1016/j.taap.2015.06.018

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Mitochondrial iron accumulation exacerbates hepatic toxicity caused by hepatitis C virus core protein2015

    • Author(s)
      Sekine S, Ito K, Watanabe H, Nakano T, Moriya K, Shintani Y, Fujie H, Tsutsumi T, Miyoshi H, Fujinaga H, Shinzawa S, Koike K, Horie T.
    • Journal Title

      Toxicol Appl Pharmacol

      Volume: 282 Issue: 3 Pages: 237-243

    • DOI

      10.1016/j.taap.2014.12.004

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 2型糖尿病時の肝臓ミトコンドリアにおける薬物障害性の解析2016

    • Author(s)
      濱田和真、桜田啓広、齋藤希衣、中埜貴文、堀江利治
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-27
    • Related Report
      2015 Annual Research Report
  • [Presentation] HCVコア蛋白質が惹起する細胞内ポルフィリン代謝異常に関する検討2016

    • Author(s)
      中埜貴文、濱田和真、森屋恭爾、小池和彦、堀江利治
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      横浜
    • Year and Date
      2016-03-27
    • Related Report
      2015 Annual Research Report
  • [Presentation] C型肝炎ウイルスが惹起する細胞内ポルフィリン代謝異常についての検討2015

    • Author(s)
      中埜貴文, 濱田和真, 森屋恭爾, 小池和彦, 堀江利治
    • Organizer
      日本薬物動態学会第30回年会
    • Place of Presentation
      東京
    • Year and Date
      2015-11-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] 生活習慣病モデル動物を用いたミトコンドリア薬物感受性の解析2015

    • Author(s)
      濱田 和真、中埜 貴文、堀江 利治
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸サンボーホール(兵庫県神戸市)
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Presentation] C型肝炎とポルフィリン症の関連性についての解析2015

    • Author(s)
      中埜 貴文、濱田 和真、森屋 恭爾、小池 和彦、堀江 利治
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸サンボーホール(兵庫県神戸市)
    • Year and Date
      2015-03-26 – 2015-03-28
    • Related Report
      2014 Research-status Report
  • [Remarks]

    • URL

      http://pharm.thu.ac.jp/research/unit/yakubutsudoutaigaku.html

    • Related Report
      2015 Annual Research Report

URL: 

Published: 2014-04-04   Modified: 2017-05-10  

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