Analysis of the molecular mechanism of hepatic GSH decrease during drug induced liver injury.

• Project/Area Number: 22790146
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Medical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: ITO Kousei 東京大学, 医学部附属病院, 准教授 (30323405)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2010: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 医療・福祉 / 薬剤反応性 / 薬剤性肝障害 / トランスポーター

Research Abstract

It is known that pretreatment of minimum amount of lipopolysaccharide(LPS) increases the animals to drug-induced liver injury, otherwise they are hardly affected by drug alone. In addition to previously proposed inflammatory cytokines produced by LPS pre-treatment, we have demonstrated that hepatic GSH decrease is an important factor cooperatively aggravates DILI in this LPS model. Moreover, species difference of the mechanism of hepatic GSH decrease after LPS treatment was emerged ; basolateral efflux of GSH was increased in rat, while metabolic pathway was somehow involved in mouse.

Research Products

• [Journal Article] Sustained intrahepatic glutathione depletion causes proteasomal degradation of multidrug resistanceassociated protein 2 in rat liver. (2012)
  • Author(s): Sekine S, Mitsuki K, Ito K, Kugioka S, Horie T.
  • Journal Title: Biochim Biophys Acta. Volume: 1822 Issue: 6 Pages: 980-987
  • DOI: 10.1016/j.bbadis.2012.01.015
  • Peer Reviewed
• [Journal Article] Itraconazole-induced cholestasis : involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4 (2011)
  • Author(s): T.Yoshikado, T.Takada, T.Yamamoto, H.Yamaji, K.Ito, T.Santa, H.Yokota, Y.Yatomi, H.Yoshida, J.Goto, S.Tsuji, H.Suzuki
  • Journal Title: Mol Pharmacol Volume: 79 Issue: 2 Pages: 241-250
  • DOI: 10.1124/mol.110.067256
  • Peer Reviewed
• [Journal Article] Sustained intrahepatic glutathione depletion causes proteasomal degradation of multidrug esistance-associated protein 2 in rat liver
  • Author(s): Sekine S, Mitsuki K, Ito K, Kugioka S and Horie T
  • Journal Title: Biochim Biophys Acta Volume: 1822 Pages: 980-987
  • Peer Reviewed
• [Journal Article] Itraconazole-induced cholestasis : involvement of the inhibition of bile canalicular phospholipid translocator MDR3/ABCB4
  • Author(s): Yoshikado T, Takada T, Yamamoto T, Yamaji H, Ito K, Santa T, Yokota H, Yatomi Y, Yoshida H, Goto J, Tsuji S and Suzuki H
  • Journal Title: Mol Pharmacol Volume: 79 Pages: 241-250
  • Peer Reviewed
• [Presentation] Hepatic glutathione decrease and inflammatory cytokines are key factors in lipopolysaccharide pre-administered drug-induced liver injury model (2012)
  • Author(s): Ito K, Ikebuchi Y, Honma M, Kozawa M, Yamamoto T and Suzuki H
  • Organizer: International Symposium on Past, Present and Future of Molecular Pharmacokinetics(PPF)
  • Place of Presentation: Integration of Basic Science, Drug Development and Regulation Tokyo, Japan
• [Presentation] Post-translational regulation of ABC transporters involved in bile flow formation. (2011)
  • Author(s): 伊藤晃成, 関根秀一, 堀江利治, 鈴木洋史
  • Organizer: 第88回日本生理学会大会 第116回日本解剖学会総会・全国学術集会
  • Place of Presentation: 横浜(シンポジウム講演 誌上開催)
  • Year and Date: 2011-03-28
• [Presentation] 薬物誘発性肝障害モデル動物における肝臓内グルタチオン量変化の重要性 (2011)
  • Author(s): 伊藤晃成,池淵祐樹,本間雅,小沢政成,山本武人and鈴木洋史
  • Organizer: 日光シンポジウム
  • Place of Presentation: 日光
• [Presentation] 酸化ストレス誘発性胆汁うっ滞時におけるMRP2の局在制御機構の解明 (2011)
  • Author(s): 関根秀一,伊藤晃成and堀江利治
  • Organizer: 第33回生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 岡山
• [Presentation] Post-translational regulation of ABC transporters involved in bile flow formation (2011)
  • Author(s): 伊藤晃成,関根秀一,堀江利治and鈴木洋史
  • Organizer: 第88回日本生理学会大会第116回日本解剖学会総会・全国学術集会
  • Place of Presentation: 横浜
• [Presentation] Hepatic glutathione and inflammatory cytokines cooperatively regulateonset of drug-induced liver injury. (2010)
  • Author(s): Ikebuchi Y, Ito K, Honma M, Kozawa M, Yamamoto T, Suzuki H.
  • Organizer: 第4回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-11-27
• [Presentation] Hepatic glutathione and inflammatory cytokines cooperatively regulate onset of drug-induced liver injury (2010)
  • Author(s): Ikebuchi Y, Ito K, Honma M, Kozawa M, Yamamoto T and Suzuki H
  • Organizer: 第4回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 東京
• [Presentation] Glutathione decrease is one of key factors for drug-induced liver injury in rats induced by lipopolysaccharide and diclofenac coadministration (2010)
  • Author(s): Ikebuchi Y, Ito K, Honma M, Kozawa M, Yamamoto T and Suzuki H
  • Organizer: 25th JSSX Annual Meeting
  • Place of Presentation: 大宮
• [Presentation] Glutathione decrease is one of key factors for drug-induced liver injury in rats induced by lipopolysaccharide and diclofenac coadministration. (2010)
  • Author(s): Ikebuchi Y, Ito K, Honma M, Kozawa M, Yamamoto T, Suzuki H.
  • Organizer: 25th JSSX Annual Meeting
  • Place of Presentation: 大宮
• [Remarks]
  • URL: http://square.umin.ac.jp/todaiyak/