Risk assessment of chemicals using chimeric mice with humanized liver

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390030
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental pharmacy
• Research Institution: Hiroshima University
• Principal Investigator: OHTA SHIGERU 広島大学, 医歯薬保健学研究院(薬), 教授 (60160503)
• Co-Investigator(Kenkyū-buntansha): SANOH Seigo 広島大学, 大学院・医歯薬保健学研究院(薬), 助教 (00552267) ; SUGIHARA Kazumi 広島国際大学, 薬学部, 教授 (20271067) ; KOTAKE Yaichiro 広島大学, 大学院・医歯薬保健学研究院(薬), 准教授 (20335649) ; FUJIMOTO Nariaki 広島大学, 原爆放射線医科学研究所, 准教授 (40243612)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: ヒト肝細胞移植キメラマウス / 化学物質 / リスク評価 / 薬物動態 / 薬物代謝

Research Abstract

Various chemicals such as the agrichemicals, industrial materials, and pharmaceuticals have been used in the worldwide. It is important to assess the risk of chemicals for humans. However, the risk assessment using experimental animals could not be enough due to species differences of toxicity between animals and humans. In this study, we conducted the risk assessment using chimeric mice with humanized liver to estimate toxicity in the human liver. It would be possible to estimate the risk assessment (hepatotoxicity) in consideration of plasma concentrations at which hepatotoxicity is observed because the predictability of pharmacokinetics of chemicals (drugs) is good in chimeric mice.

Research Products

• [Journal Article] Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics (2014)
  • Author(s): Sanoh S, Ohta S
  • Journal Title: Biopharm Drug Dispos Volume: 35(2) Pages: 71-86
  • DOI: 10.1002/bdd.1864
  • Peer Reviewed
• [Journal Article] Cell type-dependent agonist/antagonist activities of polybrominated diphenyl ethers (2013)
  • Author(s): Nakamura N, Matsubara K, Sanoh S, Ohta S, Uramaru N, Kitamura S, Yamaguchi M, Sugihara K, Fujimoto N
  • Journal Title: Toxicol Lett Volume: 223(2) Pages: 192-7
  • DOI: 10.1016/j.toxlet.2013.09.007
  • Peer Reviewed
• [Journal Article] Strain difference of oxidative metabolism of the sedative-hypnotic zaleplon by aldehyde oxidase and cytochrome P450 in vivo and in vitro in rats (2013)
  • Author(s): Tanoue C, Sugihara K, Uramaru N, Watanabe Y, Tayama Y, Ohta S, Kitamura S
  • Journal Title: Drug Metab Pharmacokinet Volume: 28(3) Pages: 269-73
  • Peer Reviewed
• [Journal Article] 2,5-Dihydroxy-4-methoxybenzophenone : a novel major in vitro metabolite of benzophenone-3 formed by rat and human liver microsomes (2013)
  • Author(s): Kamikyouden N, Sugihara K, Watanabe Y, Uramaru N, Murahashi T, Kuroyanagi M, Sanoh S, Ohta S, Kitamura S
  • Journal Title: Xenobiotica Volume: 43(6) Pages: 514-9
  • DOI: 10.3109/00498254.2012.742217
  • Peer Reviewed
• [Journal Article] Predictability of metabolism of ibuprofen and naproxen using chimeric mice with human hepatocytes (2012)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y, Uramaru N, Ohshita H, Tateno C, Horie T, Kitamura S, Ohta S
  • Journal Title: Drug Metab Dispos Volume: 40(12) Pages: 2267-72
  • DOI: 10.1124/dmd.112.047555
  • Peer Reviewed
• [Journal Article] Prediction of in vivo hepatic clearance and half-life of drug candidates in human using chimeric mice with humanized liver (2012)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Kotake Y, Tayama Y, Ohshita H, Tateno C, Horie T, Kitamura S, Ohta S
  • Journal Title: Drug Metab Dispos Volume: 40(2) Pages: 322-8
  • DOI: 10.1124/dmd.111.040923
  • Peer Reviewed
• [Journal Article] An improved thyroid hormone reporter assay to determine the thyroid hormone-like activity of amiodarone, bithionol, closantel and rafoxanide (2012)
  • Author(s): Matsubara K, Sanoh S, Ohta S, Kitamura S, Sugihara K, Fujimoto N
  • Journal Title: Toxicol Lett Volume: 208(1) Pages: 30-5
  • DOI: 10.1016/j.toxlet.2011.10.004
  • Peer Reviewed
• [Journal Article] Prediction of human metabolism of FK3453 by aldehyde oxidase using chimeric mice transplanted with human or rat hepatocytes (2012)
  • Author(s): Sanoh S, Nozaki K, Murai H, Terashita S, Teramura T, Ohta S
  • Journal Title: Drug Metab Dispos Volume: 40(1) Pages: 76-82
  • DOI: 10.1124/dmd.111.041954
  • Peer Reviewed
• [Presentation] ヒト肝細胞移植キメラマウスを用いたアロメトリックスケーリングによるヒト体内動態予測性評価 (2013)
  • Author(s): 藤本真美, 佐能正剛, 成富洋一, 佐藤公也, 河村章生, 堀口彩, 杉原数美, 北村繁幸, 堀江透, 立野知世, 太田 茂
  • Organizer: 日本薬物動態学会第28回年会
  • Place of Presentation: タワーホール船堀(東京)
  • Year and Date: 20131009-11
• [Presentation] Predictability of plasma concentration-time profiles in humans using chimeric mice with humanized liver (2013)
  • Author(s): Sanoh S, Fujimoto N, Naritomi Y, Sato K, Kawamura A, Horiguchi A, Sugihara K, Kitamura S, Horie T, Tateno C, Ohta S
  • Organizer: 10th International ISSX meeting
  • Place of Presentation: Toronto(Canada)
  • Year and Date: 20130929-1003
• [Presentation] 新生児期甲状腺ホルモン撹乱の影響-成体期肝遺伝子発現変化- (2013)
  • Author(s): 中村直樹, 佐能正剛, 松原加奈, 杉原数美, 浦丸直樹, 北村繁幸, 宮川信一, 井口泰泉, 藤本成明, 太田 茂
  • Organizer: フォーラム2013衛生薬学・環境トキシコロジー
  • Place of Presentation: 九州大学(福岡)
  • Year and Date: 20130913-14
• [Presentation] 環境化学物質による甲状腺ホルモン撹乱作用のin vitro, in vivo 評価 (2012)
  • Author(s): 松原加奈, 中村直樹, 佐能正剛, 杉原数美, 浦丸直樹, 北村繁幸, 宮川信一, 井口泰泉, 藤本成明, 太田 茂
  • Organizer: フォーラム2012衛生薬学・環境トキシコロジー
  • Place of Presentation: 名古屋
  • Year and Date: 20121025-26
• [Presentation] 環境化学物質の転写活性化を介した甲状腺ホルモン撹乱作用 (2012)
  • Author(s): 松原加奈, 佐能正剛, 藤本成明, 杉原数美, 北村繁幸, 太田 茂
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-31
• [Presentation] ヒト肝細胞移植マウスを用いたイブプロフェンの代謝, 血中動態の予測 (2012)
  • Author(s): 佐能正剛, 堀口 彩, 杉原数美, 浦丸直人, 立野知世, 堀江 透, 北村繁幸, 太田 茂
  • Organizer: 日本薬学会132年会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-30
• [Presentation] アルデヒドオキシダーゼで代謝されるFK3453 におけるヒトおよびラット肝キメラマウスを用いたヒト体内動態予測 (2011)
  • Author(s): 佐能正剛, 野崎和吉, 村井英継, 寺下茂之, 寺村俊夫, 太田 茂
  • Organizer: 第26回日本薬物動態学会
  • Place of Presentation: 広島
  • Year and Date: 2011-11-17
• [Presentation] ヒト肝キメラマウスを用いたイブプロフェンのキラル変換 (2011)
  • Author(s): 堀口 彩, 佐能正剛, 杉原数美, 立野知世, 堀江 透, 北村繁幸, 太田 茂
  • Organizer: 第26回日本薬物動態学会
  • Place of Presentation: 広島
  • Year and Date: 2011-11-17
• [Presentation] 新生仔期ラットへの甲状腺ホルモン様物質曝露による影響評価 (2011)
  • Author(s): 松原加奈, 佐能正剛, 藤本成明, 杉原数美, 北村繁幸, 太田 茂
  • Organizer: フォーラム2011衛生薬学・環境トキシコロジー
  • Place of Presentation: 金沢
  • Year and Date: 2011-10-28
• [Presentation] Prediction of PK parameters of human using human chimeric mice (2011)
  • Author(s): Sanoh S, Horiguchi A, Sugihara K, Tateno C, Horie T, Kitamura S, Ohta S
  • Organizer: 17th International Society for the Study of Xenobiotics North American Meeting
  • Place of Presentation: Atlanta, Georgia, USA
  • Year and Date: 2011-10-17
• [Presentation] ヒトおよびラット肝キメラマウスを用いた医薬品の代謝プロファイルの予測 (2011)
  • Author(s): 佐能正剛, 堀口 彩, 杉原数美, 立野知世, 堀江 透, 北村繁幸, 太田 茂
  • Organizer: 第38回日本トキシコロジー学会学術年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-07-11