| Project/Area Number |
18H02573
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Nakajima Miki 金沢大学, ナノ生命科学研究所, 教授 (70266162)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | RNA編集 / 転写後調節 / 薬物代謝 / シトクロムP450 / 核内受容体 / 転写後修飾 / 薬物代謝酵素 / microRNA / 個人差 |
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| Outline of Final Research Achievements |
Using several human hepatocarcinoma-derived cell lines, HepaRG, Huh-7, and HepG2 cells, we found that the knockdown of ADAR1 or ADAR2 by siRNA resulted in a significant decrease in CYP2B6 protein level, owing to the decreased stability of CYP2B6 mRNA. The knockdown of ADAR1 or ADAR2 resulted in a significant decrease in CYP2C8 protein level, owing to the decreased expression of HNF4a, a major transcription factor for P450s. The decrease in the HNF4a expression was considered to be a reason of the decrease in CYP2A6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 by the knockdown of ADARs. Interestingly, the knockdown of ADAR1 resulted in a significant increase in CYP3A4 protein level, owing to the increased expression of PXR, a transcription factor regulating the induction of CYP3A4. In summary, we found that A-to-I RNA editing post-transcriptionally regulates the expressions of multiple P450s, affecting pharmacokinetics and drug response.
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| Academic Significance and Societal Importance of the Research Achievements |
薬物代謝酵素は、医薬品有効成分の血中濃度を規定し、薬効や副作用発症を左右する因子として重要であり、その発現変動要因を解明する研究は、医薬品開発の効率化および医薬品適正使用の観点から社会的ニーズが高い。ヒト全遺伝子の約40％がRNA編集を受けていることが示されており、RNA編集の異常がいくつかの疾患の発症に関わっている例も知られているが、肝臓における役割はほとんど解明されていなかった。本研究では、肝臓に発現している主な薬物代謝酵素の発現制御におけるRNA編集の寄与を明らかにし、創薬や適切な薬物治療に役立つ基礎情報を提供できた。
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