Pharmacogenetic analysis of pharmacokinetic factors related with methotrexate-induced toxicity

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07063
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Hokkaido University
• Principal Investigator: Narumi Katsuya 北海道大学, 薬学研究院, 講師 (90746752)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: メトトレキサート / アルデヒドオキシダーゼ / 一塩基多型 / 肝障害

Outline of Final Research Achievements

In this study, we focused on individual differences in MTX-induced hepatic injury and investigated to clarify its mechanism. MTX-induced hepatotoxicity was enhanced by inhibition of aldehyde oxidase (AOX) activity in HepG2 cells. In addition, SNP analysis of AOX1 gene revealed that the T755I variant, found in East Asian populations, markedly decreased the enzymatic activity of AOX.The analysis based on the FAERS database revealed that concomitant use of drugs with AOX inhibitory activity increased the incidence of MTX-related hepatotoxicity.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

肝臓においてMTXはAOXを介してより毒性の低い7-OH-MTXに代謝されることが知られている。本研究の結果から、先天的にAOX活性が低い患者やAOX阻害作用を有する薬剤を併用している患者では、MTXの代謝が低下し肝毒性が増強する可能性が示された。MTXは比較的安価な薬剤であり、その汎用性を考慮すると、MTXの適正使用を指向した本研究の社会的意義は大きいと考えられる。