结合UPLC-QTOF-MS和网络毒理学技术初探补骨脂致肝毒性机制

Investigation of the mechanism of hepatotxicity induced by Fructus Psoraleae combined with UPLC-QTOF-MS and network toxicology technology

目的分析鉴定大鼠灌胃补骨脂(FP)后肝中的化学成分,结合网络毒理学初探FP致肝毒性潜在毒性机制。方法采用超高效液相色谱-四极杆飞行时间质谱(UPLC-QTOF-MS)及UNIFI数据筛查平台,快速鉴定灌胃FP后大鼠肝中的化学成分,运用多个数据库获取化学成分靶点、肝毒性靶点、成分-肝毒性共有靶点、间接靶点等信息,利用String数据库和Cytoscape 3.6.1软件对以上靶点进行蛋白质-蛋白质互作(PPI)网络构建及基因本体(GO)生物功能、京都基因和基因组百科全书数据库(KEGG)通路富集分析,筛选得到FP致肝毒性的关键靶点和潜在作用机制。结果从大鼠肝中鉴定出FP原型成分11种。网络毒理学研究表明,FP致肝毒性的潜在作用靶点共计52个,通路23条,其中ALB、HOMX1、GSR、GSTM3、CYP2C9等靶点,以及甲状腺合成途径、谷胱甘肽代谢途径与FP肝毒性有较强的相关性。结论利用UPLC-QTOF-MS结合UNIFI数据筛查平台快速鉴定了11种大鼠肝内源自FP的化学成分,通过网络毒理学研究初步预测了FP致肝毒性的潜在分子机制,为FP肝毒性的深入研究奠定了基础。

Objective To analyze and identify the chemical constituents from Fructus Psraleae(FP)in the rat liver after intragastric FP administration,and explore the potential mechanism of FP-induced hepatotoxicity via the network toxicology study.MethodsUPLC-QTOF-MS and UNIFI data screening platform were used to quickly identify the chemical constituents from FP in the rat liver afte intragastric FP administration,and multiple databases were used to search for information about chemical component targets,hepatotoxic targets,component hepatotoxic common targets and indirect targets. The construction of protein protein interaction(PPI)network and the enrichment analysis of gene ontology(GO)biological function and Kyoto Encycolpenia of Genes and Genomes(KEGG)pathway were carried out on the searched targets by using the String database and Cytoscape 3.6.1 software to explore the key targets and potential mechanism of hepatotoxicity induced by constituents from FP.ResultsEleven prototypic components of FP were identified in the rat liver. The network toxicology studies showed that there were a total of 52 potential targets and 23 pathways for the FP hepatotoxicity,among which ALB,HOMX1,GSR,GSTM3 and CYP2 C9 targets,as well as the thyroid synthesis pathway and the glutathione metabolism pathway had a strong correlation with the FP hepatotoxicity.ConclusionBy UPLC-QTOF-MS combined with the UNIFI platform,the 11 chemical constituents from FP could be quickly identified in the liver of rats that were intragastrically administered FP,and the network toxicology study has predicted potential molecular mechanism of the hepatotoxicity induced by FP.The present results provide a reference for further study the hepatotoxicity of FP.