RNA modification controlling pharmacokinetics: elucidation of the mechanisms for application to drug discovery

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02624
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Kanazawa University
• Principal Investigator: Nakajima Miki 金沢大学, ナノ生命科学研究所, 教授 (70266162)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: RNA修飾 / RNAメチル化 / 転写後調節 / 薬物代謝酵素 / シトクロム P450 / カルボキシルエステラーゼ

Outline of Final Research Achievements

Methylation of adenosine at the N6 position (m6A modification) is one of the major RNA modifications in mammals and is catalyzed by METTL3-METTL14 methyltransferase complex, called “writer” proteins. The m6A is demethylated by fat mass and obesity-associated protein (FTO) or AlkB homolog 5 (ALKBH5), called “eraser” proteins. “Reader” proteins recognize the m6A to enhance degradation of mRNA or to modulate translation or splicing, affecting the expression.
We found that the expression levels of CYP3A4, CYP2B6, and CES2, major drug-metabolizing enzymes, in human hepatoma-derived cell lines, were affected by the knockdown of m6A modification enzymes, resulting in the changes in drug metabolism potencies. We identified the m6A modification sites on CYP3A4, CYP2B6, and CES2 mRNAs that contribute to the expression changes, identified the reader proteins that recognize and act on them, and clarified the detailed molecular mechanisms.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

臨床で使用されている医薬品化合物の多くは、代謝されることで薬理作用を失い、生体外へと排泄されるため、代謝反応を担う薬物代謝酵素の発現調節機構の理解は、医薬品適正使用ならびに創薬に有益となる。本研究では、薬物代謝酵素をコードするmRNA上で、アデノシンがメチル化される修飾 （m6A修飾） が、当該薬物代謝酵素の発現量を変化させ、薬物代謝能や脂質などの生体内物質の代謝能を変動する要因となっていることを明らかにした。薬物動態の変動要因として、新たな転写後調節機構を提唱した。