Regulatory interplay between gene expression of drug-metabolizing enzymes and drug transporters

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15308
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Ritsumeikan University
• Principal Investigator: Fujino Chieri 立命館大学, 薬学部, 助教 (30844253)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 薬物代謝酵素 / 薬物トランスポーター / 遺伝子発現調節 / 薬物動態変動要因

Outline of Final Research Achievements

The aim of this study is to elucidate the regulatory interplay between gene expression of drug-metabolizing enzymes and drug transporters. In vitro and in vivo experiments revealed that decreased or deficient expression of multidrug resistance-associated protein (MRP) 2, an ATP-binding cassette transporter, resulted in decreased mRNA and protein expression of sulfotransferase (SULT) 1E1. The changes observed in downstream gene expression in the liver of MRP2-deficient rats suggested the activation of farnesoid X receptor (FXR) and liver X receptor (LXR), transcription factors. Bile acid, an agonist of FXR, decreased gene expression of SULT1E1 in human hepatocellular carcinoma cell line. These results suggest that decreased MRP2 expression may affect SULT1E1 expression via activation of transcription factors by endogenous substances.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

薬物代謝酵素や薬物トランスポーターの遺伝子発現が変動することで医薬品の体内動態が変動し、薬効や副作用発現に影響を与えることがある。本研究において、MRP2の発現低下がSULT1E1の発現に影響を及ぼす可能性を示した。MRP2には遺伝子多型が存在することが知られており、MRP2の発現が低い人においてMRP2基質だけではない医薬品の体内動態の変動に注意する必要があると考えられる。このような生理的な遺伝子発現の相互調節が明らかになることで、臨床現場や創薬段階での薬物投与における、薬物動態の変動要因や個人差の予測に役立つと考えられる。