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  

Metabolomic study on the susceptible factors of idiosyncratic Traditional Chinese Medicine-induced liver injury: Exemplification of a Polygonum multiflorum preparation

作　　者：周元园 牛明[2] 涂灿[1,2] 卫璐戈 葛斐林 张乐[1,2] 王肖辉 李春雨[3] 刘晓熠 张雅铭[2] 唐怡[1] 肖小河[2] 王伽伯[2] Yuanyuan Zhou;Ming Niu;Can Tu;Luge Wei;Feilin Ge;Le Zhang;Xiaohui Wang;Chunyu Li;Xiaoyi Liu;Yarning Zhang;Yi Tang;Xiaohe Xiao;Jiabo Wang(School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China;China Military' Institute of Chinese Medicine,302 Military Hospital,Beijing 100039,China;Cancer Hospital of Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100021,China)

机构地区：[1]成都中医药大学药学院,成都611137 [2]解放军302医院全军中医药研究所,北京100039 [3]中国医学科学院北京协和医学院肿瘤医院,北京100021

出　　处：《科学通报》2019年第9期948-962,共15页Chinese Science Bulletin

基　　金：国家重大新药创制专项(2015ZX09501-004-001-008);国家自然科学基金(81503247);北京市科技新星计划(Z16111000490000);国家公益性行业专项(201507004-04);国家中药标准化项目(ZYBZH-Y-BJ-07)资助

摘　　要：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.综合提示代谢重编程可能是药物特异质肝损伤易感性的重要机制之一.基于易感因素相关的代谢紊乱通路,筛选发现了亚油酸、骨化二醇、18-羟基皮质酮等10个生物标志物可较好地识别易感模型动物(ROC分析中AUC均大于0.9),对临床识别易感人群具有潜在的应用价值.The underlying mechanism(s) that govern idiosyncratic drug-induced liver injury(IDILI) have remained poorly defined. Several studies have shown that IDILI was caused by body diathesis, environment, metabolism, immunization, etc. However, the underlying mechanism(s) of IDILI was still ambiguous, which led to an unsolved issue in clinical toxicology. Understanding of such mechanisms is critical not only for the prevention of such DILI adverse effect as well as the clinical diagnosis, intervention or management of the affected individuals. In this study, we carried out a metabolomic study on mice treated with Runzao Zhiyang Capsule(RZZY), since Polygonum multiflorum, a key ingredient in this preparation, is known to cause DILI. Clinical case analysis showed that a small number of patients developed drug-induced liver injury(DILI) in a dose-independent manner. Meanwhile, the affected individuals often exhibited skin conditions associated with features of abnormal inflammatory responses. In normal mice, treatment with RZZY alone had no significant effects on biochemical indices of liver function, including aspartate aminotransferase(AST) and alanine aminotransferase(ALT) activities. At the same time, it had no significant effects on liver histopathology either. Moreover, we used non-toxic dose of lipopolysaccharide(LPS) pretreatment to produce mild inflammatory stress mice model, which showed no significant liver injury phenotype, except for a small number of inflammatory immune cells infiltration in portal areas of liver. However, by metabolomics profiling, we found significant alterations of plasma metabolites in the LPS treated mice, including up-regulated histidine and alanine metabolic pathways(P<0.01) and significantly down-regulated tryptophan metabolic pathways(P<0.01), etc. These results suggested that metabolic reprogramming might be an important underlying mechanism for susceptibility of liver injury. On the other side, the mice co-treated with RZZY and LPS induced significant liver injury phenotype, accomp

关 键 词：药物特异质肝损伤 何首乌 易感因素 免疫应激 代谢组学 代谢重编程 

分 类 号：R285[医药卫生—中药学]