Analysis of the transport of active metabolites by hepatic efflux transporters and identification of physiological substrates using machine learning-based metabolomics

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06688
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kanazawa University
• Principal Investigator: Masuo Yusuke 金沢大学, 薬学系, 准教授 (90708140)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 排出輸送体 / トランスポーター / BCRP / MRP3 / 肝細胞 / AAV

Outline of Final Research Achievements

BCRP/ABCG2 and MRP3/ABCC3 are expressed in the canalicular and sinusoidal plasma membranes of hepatocytes, respectively, and pump out substrates from the liver. These transporters are also expressed in small intestine and kidney, but their hepatic roles were unclear. Using adeno-associated virus (AAV) to deliver shRNA, mice with liver-specific knockdown of Bcrp or Mrp3 were constructed. Knockdown of Bcrp resulted in increased plasma concentrations of the BCRP substrate sulfasalazine, while knockdown of Mrp3 reduced the hepatic efflux of the MRP3 substrate acetaminophen glucuronide into the blood. This study demonstrates that AAV-mediated liver-specific knockdown is a useful tool for evaluating the functions of hepatic transporters.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

肝で生成した活性代謝物は、血液中へ排出輸送された後に全身で薬理作用を示すが、その輸送機構が解明された例は乏しい。本研究成果は、AAVを用いて肝での膜輸送体の発現を選択的に制御することで、肝に発現する膜輸送体の機能をin vivoで簡便に評価する実験系を構築でき、今後の普遍的な機能評価に活用できる点で社会的意義がある。