基于Nrf2/MRP2信号轴介导的转运调控探讨甘草对黄药子肝损伤的减毒作用机制

临床实践表明黄药子对甲状腺疾病和癌症的疗效显著，但长期或大剂量服用黄药子及含黄药子的制剂可导致蓄积性肝损伤。现代研究揭示Nrf2/MRP2信号轴介导的转运调控是对抗肝损伤的有效途径，临床及前期研究均显示甘草对黄药子肝损伤具有显著的保护作用，而甘草可以激活Nrf2/MRP2信号轴介导的转运调控。据此提出“甘草可能通过激活Nrf2/MRP2信号轴介导的转运调控对黄药子肝损伤发挥减毒作用”的科学假说。本项目拟在前期工作基础上，从信号轴-毒效成分转运角度，分别在HepG2细胞、Nrf2−/−型HepG2细胞及小鼠整体水平上，从细胞功能、生化指标、组织形态学、Nrf2蛋白和药物转运体MRP2的转录与表达、毒效成分PK过程等进行多指标整合分析，阐释甘草对黄药子肝损伤的减毒作用机制。本项目研究将为黄药子的临床安全应用提供重要的科学支撑，并为甘草配伍有毒中药的减毒作用机制研究提供探索性思路与方法。

Clinical practice shows that Rhizoma Dioscoreae Bulbiferae has remarkable curative effect on thyroid disease and cancer. However, long-term or high-dose use of Rhizoma Dioscoreae Bulbiferae and its preparations can cause cumulative liver damage. Studies have revealed that the transport regulation mediated by the Nrf2/MRP2 signal axis was an effective way to combat liver injury. Clinical and previous studies have found that licorice has a significant protective effect on the liver injury induced by Rhizoma Dioscoreae Bulbiferae, and licorice can activate the transport regulation mediated by the Nrf2/MRP2 signal axis. The scientific hypothesis was put forward that licorice may attenuate liver injury induced by Rhizoma Dioscoreae Bulbiferae by activating the transport regulation mediated by Nrf2/MRP2 signal axis. On the basis of previous work, from the perspective of signal axis-toxic components transport, HepG2 cells, Nrf2−/− HepG2 cells and mice were used in this project, and multi-index integrated analysis was carried out from cell function, biochemical indexes, histomorphology, transcription and expression of Nrf2 protein and drug transporter MRP2, and the pharmacokinetics processes of toxic components, which was applied to explain the attenuated mechanism of licorice on liver injury iduced by Rhizoma Dioscoreae Bulbiferae. This research will provide important scientific support for the safe clinical application of Rhizoma Dioscoreae Bulbiferae, and provide exploratory ideas and methods for the study of the attenuated mechanism of licorice in combination with toxic traditional Chinese medicines.