中药特异质肝损伤易感因素的代谢组学研究: 以何首乌制剂为例

The susceptibility mechanism of drug-induced idiosyncratic liver injury is a current difficulty in clinical toxicology research. In this study, taking the Polygonum multiflorum preparation - Runzao Zhiyang Capsule as an example, combined with clinical case analysis, metabolomics was used to explore the possible susceptibility mechanism of its liver injury. Case analysis showed that the liver injury related to Runzao Zhiyang Capsule has a relatively typical idiosyncratic property and is related to abnormal immune activation. In normal mice, intragastric administration of Runzao Zhiyang Capsule had no significant impact on liver function biochemical indexes and liver tissue pathology; in susceptible model mice, the immune stress modeling factor did not cause a liver injury phenotype, only accompanied by a small amount of inflammatory immune cell infiltration in the liver tissue, but from metabolomics, it could be seen that metabolic pathways such as histidine and alanine were significantly up-regulated (P < 0.01) and metabolic pathways such as tryptophan were significantly down-regulated (P < 0.01), suggesting that metabolic reprogramming may be an important internal mechanism of the susceptibility factors for its liver injury; and on the basis of immune stress susceptibility factors, intragastric administration of Runzao Zhiyang Capsule caused a significant liver injury phenotype, accompanied by a large amount of inflammatory immune cell infiltration and inflammatory reaction in the liver tissue, and at the same time, metabolomics also showed significant changes in inflammation-related metabolic pathways such as arachidonic acid, linoleic acid, glycerophospholipids, bile acids, etc. Comprehensive indication of metabolic reprogramming

药物特异质肝损伤的易感机制是当前临床毒理学研究的难点. 本研究以何首乌制剂——润燥止痒胶囊为例, 结合临床病例分析, 采用代谢组学探讨其肝损伤可能的易感机制. 病例分析表明润燥止痒胶囊相关肝损伤具有较典型的特异质属性, 且与免疫异常活化有关. 在正常小鼠上, 灌胃润燥止痒胶囊对肝功能生化指标和肝组织病理无显著影响; 在易感模型小鼠, 免疫应激造模因素并未引起肝损伤表型, 仅伴随肝组织少量炎性免疫细胞浸润, 但从代谢组学可见组氨酸和丙氨酸等代谢通路显著上调(P<0.01)和色氨酸等代谢通路显著下调(P<0.01), 提示代谢重编程可能是其肝损伤易感因素的重要内在机制; 而在免疫应激易感因素基础上, 灌胃润燥止痒胶囊引起了显著的肝损伤表型, 并伴有肝组织大量炎性免疫细胞浸润和炎症反应, 同时代谢组学上亦表现为花生四烯酸、亚油酸、甘油磷脂、胆汁酸等与炎症相关代谢通路的显著改变. 综合提示代谢重编