消炎利胆片调控胆汁酸代谢稳态与氧化应激防御通路治疗湿热证胆汁淤积的作用机制及配伍研究

依据胆汁淤积药物作用机制最新进展和中医药“保肝利胆”的特色优势，结合前期基础，本项目提出“内源性胆汁酸代谢失衡与胆汁淤积病程密切相关；干预胆汁淤积状态下机体胆汁酸合成、代谢转运，以促进胆汁排泄，启动内源性抗氧化应激通路调控下游保护性细胞因子的表达，以抵抗肝损伤，可能是消炎利胆片治疗湿热证胆汁淤积的重要机制；三味苦寒药物相须配伍，具有协同效应”的科学假说。项目拟采用代谢组学(内源性胆汁酸代谢组学)方法，阐明胆汁淤积与胆汁酸代谢失衡的关系；采用组织形态学、分子生物学(受体、转运体、炎症因子的表达)、体内药物分析学(药效成分代谢、分布、消除特征)，从干预FXR通路，促进胆汁外排和启动Nrf2通路保护肝损伤两个方面，阐明消炎利胆片治疗胆汁淤积的作用机制(途径及靶点)；从不同配伍的拆方样品对整体药效、靶点以及药效成分体内过程的影响等三个层面，揭示组方的配伍原理。为消炎利胆片的合理用药提供科学依据。

According to recent advance for mechanism research and theoretical advantages of Chinese Medicines for cholestasis, together along with our previous researches, we present the scientific hypothesis for this project as “Metabolic disequilibrium of endogenous bile acids is closely related with cholestasis diseases. The possible curative mechanisms of Xiaoyan Lidan Tablets for these diseases would be by promoting bile excretion with regulating synthese, metabolism and transportation of bile acids, and protecting liver by activating anti-oxidative stress pathway with coordinating effects of three drugs of Bitter and Cold in nature.” Therefore, metabonomic characters of endogenous bile acids, intervening effects upon targets of FXR (farnesoid X receptor) and Nrf2 (nuclear factor erythroid 2) relating signaling pathways and Kinetics characters of Xiaoyan Lidan Tablets and different drug combinations would be investigated and compared systematically. The results are prospected to clarify the mechanisms for pharmacological and compatibility mechanisms of Xiaoyan Lidan Tablets for cholestasis of Damp-heat syndrome, and apply scientific guidance for clinical use.