2013 Fiscal Year Annual Research Report
化学物質による細胞内受容体―異物代謝酵素シグナル伝達系撹乱の感受性支配因子の解明
| Project/Area Number |
21221004
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| Research Institution | Ehime University |
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Principal Investigator |
岩田 久人 愛媛大学, 沿岸環境科学研究センター, 教授 (10271652)
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| Co-Investigator(Kenkyū-buntansha) |
阿草 哲郎 愛媛大学, 沿岸環境科学研究センター, 特任助教 (50403853)
宮崎 龍彦 岐阜大学, 医学部附属病院, 教授 (80239384)
鈴木 賢一 広島大学, 理学(系)研究科(研究院), 特任助教 (90363043)
石橋 弘志 尚絅大学短期大学部, 食物栄養学科, 准教授 (90403857)
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| Project Period (FY) |
2009-05-11 – 2014-03-31
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| Keywords | 化学物質 / 細胞内受容体 / 異物代謝酵素 / 感受性 |
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| Research Abstract |
これまでに本研究課題で構築してきたin vitro CYP誘導レポーター遺伝子アッセイ・SPRアッセイ・FRETアッセイ系を利用して、今年度はより多くの化学物質のスクリーニングを試みた。これらのアッセイによって得られた化学物質と細胞内受容体との相互作用については、50％影響濃度（EC50）やCYP誘導等価係数（IEF）を指標にして評価した。さらに、野生鳥類（カワウ・アホウドリ）・哺乳類（アザラシ）を対象に、in vitro CYP誘導アッセイ系を用いて得られた化学物質の用量-応答曲線と各野生個体群の肝臓での化学物質蓄積量とCYP発現量の関係は一致することが明らかとなった。以上の結果より、in vitro CYP誘導アッセイ系を適用することにより、種特異的感受性を考慮した野生個体群のリスクが評価できることを立証した。
また、鳥類や陸棲・水棲哺乳類の肝ミクロソームに由来するCYPの包括的なin vitro代謝実験系を確立した。これにより、PCB・エストロジェンの代謝物の同定・定量をおこなった。各CYP分子種の代謝力については、in vitro代謝実験とin silico基質-CYP結合モデルから評価し、種特異的な代謝力を規定するアミノ酸残基を特定することができた。
この他、ダイオキシン類曝露に対して敏感な系統マウスと鈍感な系統マウスでAHRと相互作用するタンパク質に質的・量的な差異があるかどうかについて、pull-down法とMALDI-TOF/TOF質量分析法を組み合わせた実験系で検証した。その結果、感受性を規定する候補タンパク質の同定に成功した。その候補タンパク質をin vitro CYP誘導アッセイ系で強制発現させ、ダイオキシン類曝露に対するAHR依存的な反応を測定したところ、感受性が変化することを確認した。したがって、本候補タンパク質は感受性規定因子であると結論された。
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| Current Status of Research Progress |
Reason
25年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
25年度が最終年度であるため、記入しない。
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