Involvement of metabolic enzymes and transporters in diclofenac-induced liver injury

• Project/Area Number: 23590210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kinki University
• Principal Investigator: IWAKI Masahiro 近畿大学, 薬学部, 教授 (30140346)
• Co-Investigator(Kenkyū-buntansha): 山下 哲生 (80444727) ; 川瀬 篤史 近畿大学, 薬学部, 講師 (80411578)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 薬物動態・代謝学 / 肝毒性 / トランスポーター / 代謝酵素 / 反応性代謝物 / siRNA / アシルグルクロナイド

Research Abstract

We examined the involvement of CYP2C9, UGT2B7, MRP2 and MRP3 in induction of diclofenac (DF)-induced hepatotoxicity. In primary cultured rat hepatocytes, the knockdown for MRP2 resulted in the accumulation of DF-Glu to cells. Whereas, the knockdown for MRP3 exhibited little alterations in the accumulation of DF-Glu to cells. The higher hepatotoxicity was observed in MRP2 knockdown cells compared with MRP3 knockdown cells, suggesting that MRP2 is more important in induction of hepatotoxicity by DF.