从物质-代谢-毒性关联视角多维度解析雷公藤复方配伍“异类相制”减轻肝损伤机制

Multi-Dimensional Analysis of the Mechanism of Tripterygium Wilfordii Hook.f.Compound Prescription Based on"Heterogeneous Restriction"in Reducing Hepatotoxicity from the Perspective of Substance-Metabolism-Toxicity Correlation

雷公藤是治疗风湿免疫病的常用药物,但其毒副作用明显。根据雷公藤复方临床应用实践所提出的“异类相制”理论,以清络通痹方为载体,选择临床常见的肝毒性为切入点,从物质-代谢-毒性关联视角多维度探索雷公藤复方配伍“异类相制”减轻肝损伤机制。清络通痹方配伍能调节雷公藤自身代谢和内源性糖脂代谢而发挥减毒效应;通过调控核受体-代谢酶、Nrf1-线粒体和Nrf2-抗氧化途径,改善脂质过氧化损伤、线粒体损伤和肝细胞过度自噬与凋亡,从而起到保护肝脏的作用;不同功效药物配伍通过细胞、分子调控网络的不同环节、不同靶点发挥的减毒效应也体现了“异类相制”的特征。为方药配伍理论源头创新及指导雷公藤的临床安全合理应用提供科学依据。

Tripterygium wilfordii Hook.f.(TWHF)is a commonly used Chinese medicine for the treatment of rheumatic immune diseases,but its side effects are obvious.Based on the theory of"heterogeneous restriction"proposed by the clinical application of TWHF compound prescriptions,with Qingluo Tongbi Fomula as a carrier,and clinically frequent hepatotoxicity as the starting point,the mechanism of TWHF compound compatibility to reduce liver injury was explored from the perspective of substance-metabolism-toxicity correlation in multiple dimensions.Qingluo Tongbi Fomula could reduce TWHF-induced hepatotoxicity by regulating the metabolism of TWHF and endogenous glucose and lipid,and improving lipid peroxidation damage,mitochondrial damage,and liver cell excessive autophagy and apoptosis via nuclear receptors-metabolizing enzymes,Nrf1-mitochondria and Nrf2-antioxidant pathways.The detoxicity effect of Chinese medicines with different functions through different links and targets of the cell and molecular regulatory network reflected the characteristics of"heterogeneous restriction".This research has provided a scientific basis for the original innovation of the theory of prescription compatibility and guiding the safe and reasonable clinical application of TWHF.