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。
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.
作者
崔媛
李海山
宋乃宁
李斌
隋峰
李鹰飞
郭家宾
贾强
李桦
高月
沈国林
CUI Yuan;LI Haishan;SONG Naining;LI Bin;SUI Feng;LI Yingfei;GUO Jiabin;JIA Qiang;LI Hua;GAO Yue;SHEN Guolin(Institute of Chemicals Safety,Chinese Academy of Inspection and Quarantine, Beijing 100123, China;Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China;Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China;The National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing 100050, China;Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100170, China;Center of Disease Control and Prevention, PLA, Beijing 100071, China;Shandong Academy of Occupational Health and Occupational Medicine, Shandong Jinan 250062, China)
出处
《中国药物警戒》
2019年第8期449-466,共18页
Chinese Journal of Pharmacovigilance
基金
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
