2021 Fiscal Year Final Research Report
Integration analysis between RNA editing and circadian clock system for elucidation of interindividual variation of drug pharmacokinetics
| Project/Area Number |
18H04019
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 47:Pharmaceutical sciences and related fields
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Keywords | 概日リズム / RNA編集 / 薬物代謝酵素 / トランスポーター / 個体間変動 / 個体内変動 |
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| Outline of Final Research Achievements |
Daily variations in biological functions are important factors affecting the efficacy and toxicity of drugs; a large number of drugs cannot be expected to have the same potency at different administration times. Dosing time-dependent differences in the therapeutic effects of drugs are, at least in part, due to diurnal changes in drug disposition such as absorption, distribution, metabolism and elimination. The expression and function of several xenobiotic transporters and drug metabolism enzymes exhibit diurnal variation, resulting in dosing time-dependent differences in drug disposition. The present study demonstrated that adenosine deaminase acting on RNA (ADAR) was involved in the circadian regulation of xenobiotic transporters and drug metabolism enzymes in human renal proximal tubular epithelial cells and hepatic cells. ADAR1 regulate the expression of these pharmacokinetics-related factors through modulating the transcription, translation, formation of splicing variant.
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| Free Research Field |
時間薬剤学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の成果によりADARが多岐に渡るメカニズムによって主要なトランスポーターや代謝酵素の概日リズムや機能を制御していることが明らかになり、医薬品の効果や副作用に時刻の違いによる差異が生じる原因の一部を解明することに成功した。また、RNAシーケンス解析の結果、ヒトのRNA上にはADARによって時刻依存的に編集される部位が数万箇所は存在し、様々な遺伝子の発現や機能に影響を及ぼしている可能性も示唆された。今後、このようなADARの活性リズムが、他の薬効関連分子の発現にどのような影響を及ぼしているのかを解明することで、医薬品の効果・副作用の個体差と個体内変動の理解に繋がることが期待される。
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