中国药物警戒 ›› 2019, Vol. 16 ›› Issue (8): 449-466.

• 基础与临床研究 •    下一篇

马兜铃酸I影响小鼠肝脏脂肪酸β氧化和糖代谢以及TCA循环的代谢组学研究

崔媛1, 李海山1, 宋乃宁1, 李斌4, 隋峰5, 李鹰飞5, 郭家宾6, 贾强7, 李桦3, 高月2, 沈国林1,*   

  1. 1 中国检验检疫科学研究院化学品安全研究所,北京 100123;
    2 军事科学院军事医学研究院辐射医学研究所,北京 100850;
    3 军事科学院军事医学研究院毒物药物研究所,北京 100850;
    4 中国疾病预防控制中心职业卫生与中毒控制所,北京 100050;
    5 中国中医科学院中药研究所,北京 100170;
    6 中国人民解放军疾病预防控制中心,北京 100071;
    7 山东省职业卫生与职业病防治研究院,山东 济南 250062
  • 收稿日期:2019-09-09 修回日期:2019-09-09 出版日期:2019-08-20 发布日期:2019-09-09
  • 通讯作者: *沈国林,男,副研究员,化学品安全。E-mail：shengl@aqsiqch.ac.cn
  • 作者简介:崔媛,女,助理研究员,化学品安全。
  • 基金资助:
    公益性科研院所基本科研业务费专项资金资助项目（2018JK023、2018JK021、2017JK042）：双酚A基于肝脏代谢酶与核受体的代谢机制研究、化学品毒性评价新模型的建立及其应用研究、基于毒性整体早期评价的典型高关注化学物质肝毒性生物标志物筛选关键技术研究; 国家重点研发计划（2017YFF0211201）：化学品健康危害快速分级与确证技术研究

Metabonomics Reveals that Aristolochic Acid I Affects β-oxidation of Fatty Acids, Glucose Metabolism and the TCA Cycle in the Mice Liver

CUI Yuan1, LI Haishan1, SONG Naining1, LI Bin4, SUI Feng5, LI Yingfei5, GUO Jiabin6, JIA Qiang7, LI Hua3, GAO Yue2, SHEN Guolin1,*   

  1. 1 Institute of Chemicals Safety,Chinese Academy of Inspection and Quarantine, Beijing 100123, China;
    2 Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China;
    3 Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China;
    4 The National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China;
    5 Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100170, China;
    6 Center of Disease Control and Prevention, PLA, Beijing 100071, China;
    7 Shandong Academy of Occupational Health and Occupational Medicine, Shandong Jinan 250062, China
  • Received:2019-09-09 Revised:2019-09-09 Online:2019-08-20 Published:2019-09-09

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摘要： 目的 利用代谢组学技术结合分子生物学技术找出马兜铃酸I影响小鼠肝脏代谢产生的差异性内源性物质,找出影响最相关的代谢通路,系统揭示马兜铃酸I影响小鼠肝脏代谢功能的作用机制。方法 雄性6周龄C57BL/6 小鼠作为研究对象,按照设定的马兜铃酸I剂量（0.2、2、10、20 mg·kg-1）,随机分为4个给药组和l个正常对照组,灌胃给药,每周5天,连续4周。利用代谢组学技术结合生理学、病理学、分子生物学、酶学、药物代谢和系统生物学的相关技术和手段揭示马兜铃酸I影响小鼠肝脏代谢功能的作用机制。结果 马兜铃酸I影响肝脏代谢功能的作用机制是马兜铃酸I能够促进肝脏细胞中葡萄糖的酵解过程,提高肝脏细胞对脂肪酸的摄取功能,抑制糖异生作用和脂肪酸的β氧化,阻碍TCA循环,最终引起小鼠肝脏微环境代谢的紊乱。结论 本研究基于代谢组学的分析技术,结合生物信息学分析手段,从全新角度阐明了马兜铃酸I影响肝脏代谢功能的作用机制。

关键词: 马兜铃酸I, 代谢组学, 代谢通路, 线粒体, TCA循环

Abstract: Objective To reveal the differential endogenous substances generated via hepatic metabolism stimulated by aristolochic acid I and the most relevant metabolic pathways using metabonomics combined with molecular biotechnology. Furthermore, to systematically explore the mechanism by which aristolochic acid I affects hepatic metabolic functions in mice. Methods Six-week-old male C57BL/6 mice were randomly divided into four groups of different doses of aristolochic acid I: 0.2, 2, 10 and 20 mg·kg-1, and one untreated control group. The drug was administrated by gavage, 5 days/week for 4 consecutive weeks. Metabonomics technology combined with physiology, pathology, molecular biology, enzymology, drug metabolism and systems biology were used to explore the mechanism by which aristolochic acid I affects hepatic metabolic functions in mice. Results Aristolochic acid I affected hepatic metabolism by promoting glycolysis in hepatocytes, improving the fatty acid uptake function of hepatocytes, inhibiting gluconeogenesis and β oxidation of fatty acid, impeding the TCA cycle, and finally leading to hepatic microenvironment metabolic disorder. Conclusion Based on metabonomics combined with bioinformatics, the mechanism by which aristolochic acid I affected hepatic metabolic functions was illuminated from a new perspective.

Key words: aristolochic acid I, metabonomics, metabolic pathway, mitochondrion, TCA cycle

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