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基于网络毒理学和分子对接筛选何首乌致肝毒性成分和CYP450抑制剂

Screening of Hepatotoxic Components and CYP450 Inhibitors of Polygoni Multiflori Radix Based on Network Toxicology and Molecular Docking

  • 摘要: 基于网络毒理学和分子对接技术分析何首乌致肝毒性的成分和作用机制。首先,通过GEO数据库中肝损伤基因集和CTD数据库共收集到497个肝毒性靶点。其次,通过文献检索及CTD数据库筛选得到30个何首乌的毒性成分,通过CTD数据库和SWISS数据库预测毒性成分作用靶点,选取毒性成分作用靶点与肝毒性靶点的59个重叠靶点作为何首乌毒性成分的肝毒性作用靶点,并通过CytoHubba软件从中筛选出30个核心靶点。然后,采用STRING数据库分析靶点间的相互作用,通过DAVID数据库进行GO/KEGG富集分析,发现毒性成分的作用靶点主要富集在228个GO条目及34条信号通路。通过Cytoscape软件建立“毒性成分-作用靶点-信号通路”网络。最后,通过Discovery Studio软件虚拟筛选与CYP酶结合的毒性成分,分子对接结果发现,表没食子儿茶素没食子酸酯、羟基大黄素、儿茶素等与CYP1A1、CYP1A2、CYP2E1、CYP2B6、CYP2C9、CYP3A4结合能力较强,这些成分极有可能通过抑制CYP450同工酶活性诱导肝脏毒性。

     

    Abstract: The components of Polygoni Multiflori Radix, and its hepatotoxic mechanism were investigated by network toxicology and molecular docking technology. Firstly, a total of 497 hepatotoxicity targets were collected from the LIVER injury gene set in GEO database and the CTD database. Secondly, thirty toxic components of Polygoni Multiflori Radix were searched by literature and screened by CTD database. CTD database and SWISS database were used to predict the targets of toxic components. 59 overlapping targets of toxic components targets and the hepatotoxic targets were regarded as the hepatotoxic targets of the toxic components in Polygoni Multiflori Radix. 30 core targets were screened by Cytohubba. Then, the interaction network of hepatotoxic targets of the toxic components was analyzed by STRING database, and GO/KEGG analysis was performed by DAVID platform.It was found that the targets of toxic components were mainly concentrated in 228 GO entries and 34 signaling pathways. The network of "toxic components-hepatotoxic targets-signal pathways" was constructed by Cytoscape.Finally, the toxic components which were docked to CYP enzyme were virtually screening by Discovery Studio. The results of molecular docking showed that epigallocatechin gallate, hydroxyemodin and catechin had strong binding ability with CYP1A1, CYP1A2, CYP2E1, CYP2B6, CYP2C9 and CYP3A4. These components were likely to induce hepatotoxicity by inhibiting CYP450 isoenzyme activity.

     

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