中国药物警戒 ›› 2024, Vol. 21 ›› Issue (11): 1216-1223.
DOI: 10.19803/j.1672-8629.20240472

• 药源性心脏毒性研究专栏（二） • 上一篇    下一篇

基于网络药理学和非靶向代谢组学的吴茱萸心脏毒性研究

殷晓阳1, 张晓朦1,2, 刘泽宇1, 刘亚迪1, 王雨1,2, 林志健1,2, 张冰1,2,*   

  1. 1北京中医药大学中药学院,北京 102488;
    2北京中医药大学中药药物警戒与合理用药研究中心,北京 102488
  • 收稿日期:2024-07-11 出版日期:2024-11-15 发布日期:2024-11-20
  • 通讯作者: *张冰,女,博士,主任医师·博导,中药药物警戒与合理用药。E-mail：zhangb@bucm.edu.cn
  • 作者简介:殷晓阳,女,在读硕士,中药药物警戒与合理用药。
  • 基金资助:
    国家自然科学基金资助项目（82274117）; 国家中医药管理局高水平重点学科建设项目-临床中药学（zyyzdxk-2023257）

Cardiotoxicity of Euodia rutaecarpa(Juss.) Benth. Based on Network Pharmacology and Untargeted Metabolomics

YIN Xiaoyang1, ZHANG Xiaomeng1,2, LIU Zeyu1, LIU Yadi1, WANG Yu1,2, LIN Zhijian1,2, ZHANG Bing1,2,*   

  1. 1School of Chinese Materia Medica, Beijing University of Traditional Chinese Medicine, Beijng 102488, China;
    2Center for Pharmacovigilance and Rational Use of Chinese Medicine, Beijing University of Chinese Medicine, Beijng 102488, China
  • Received:2024-07-11 Online:2024-11-15 Published:2024-11-20

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摘要： 目的 以用药历史悠久的吴茱萸为示例,探索其心脏毒性潜在作用机制,为其临床用药安全与风险防控提供警戒。方法 利用网络药理学技术分析吴茱萸作用于心脏的靶点通路,结合非靶向代谢组学技术探讨吴茱萸对心脏代谢通路的影响,分析其对心脏毒性的潜在作用机制。结果 网络药理学分析得到吴茱萸和心脏毒性的交集靶点有51个,其中包括TNF、IL-6、IL-1β、TP53、CASP3等核心靶点,涉及高级糖基化终末产物-受体（AGE-RAGE）,丝裂原活化蛋白激酶（MAPK）等信号通路;代谢组学分析筛选出嘌呤代谢途径,缬氨酸、亮氨酸和异亮氨酸的生物合成途径,柠檬酸盐（TCA）循环途径等关键代谢通路。综合分析网络药理学预测结果与非靶向代谢组学结果,提示吴茱萸引起的心脏毒性与能量代谢有关,可能通过干扰心肌细胞内TCA循环、嘌呤代谢以及蛋白质的合成分解引起心脏毒性。结论 吴茱萸的心脏毒性与影响心肌能量代谢密切相关,且由于其对心脏有双向作用,临床用药应注意用量、证候等,加强用药监护。

关键词: 吴茱萸, 心脏毒性, 药物警戒, 网络药理学, 非靶向代谢组学

Abstract: Objective To explore the potential mechanisms of cardiotoxicity of Euodia rutaecarpa, a long-used traditional Chinese medicine, in order to contribute to clinical safety and risk prevention. Methods Network pharmacology was employed to analyze the target pathways of Euodia rutaecarpa that acted on the heart. In combination with untargeted metabolomics, the impact of Euodia rutaecarpa on cardiac metabolic pathways was investigated in order to find out about the potential mechanisms of cardiotoxicity. Results Network pharmacology identified 51 intersecting targets between Euodia rutaecarpa and cardiotoxicity, such as TNF, IL-6, IL-1β, TP53, and CASP3. These targets were involved in key signaling pathways such as the Advanced Glycation End Products-Receptor (AGE-RAGE) and Mitogen-Activated Protein Kinase (MAPK) pathways. Metabolomics analysis revealed metabolic pathways, including purine metabolism, biosynthesis of valine, leucine, and isoleucine, and the citric acid (TCA) cycle. The combination of network pharmacology and untargeted metabolomics suggested that the cardiotoxicity of Euodia rutaecarpa was related to myocardial energy metabolism, potentially via the disruption of the intracellular TCA cycle, purine metabolism, and protein synthesis and degradation. Conclusion The cardiotoxicity of Euodia rutaecarpa is closely related to its impact on myocardial energy metabolism and exhibits bidirectional effects on the heart. Clinicians should be cautious regarding dosage and symptoms while attaching importance to drug monitoring.

Key words: Euodia Rutaecarpa (Juss.) Benth., Cardiotoxicity, Pharmacovigilance, Network Pharmacology, Untargeted Metabolomics

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