不同种间、性别和年龄小鼠肝脏代谢谱的差异研究  

Study on the Difference of Liver Metabolism Spectrum among Different Species, Sexes and Ages of Mice

作　　者：李海山[1] 姬海南 宋乃宁[1] 李斌[2] 隋峰[3] 李鹰飞 郭家彬 贾强[5] 李桦 高月 沈国林[1] LI Haishan;JI Hainan;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;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,Jinan Shandong,250062,China;Institute of Pharmacology and Toxicology,Academy of Military Medical Sciences Beijing,100850,China;Institute of Radiation Medicine,Academy of Military Medical Sciences,Beijing 100850,China)

机构地区：[1]中国检验检疫科学研究院化学品安全研究所,北京100123 [2]中国疾病预防控制中心职业卫生与中毒控制所,北京100050 [3]中国中医科学院中药研究所,北京100170 [4]中国人民解放军疾病预防控制中心,北京100071 [5]山东省职业卫生与职业病防治研究院,山东济南250062 [6]军事科学院军事医学研究院毒物药物研究所,北京100850 [7]军事科学院军事医学研究院辐射医学研究所,北京100850

出　　处：《中国药物警戒》2020年第1期6-16,共11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(2017JK047)：靶向代谢组学技术及试剂盒的开发;化学品毒性评价新模型的建立及其应用研究(2018JK021);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(2017JK042);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

摘　　要：目的利用代谢组学等相关技术研究不同种间、性别和年龄小鼠肝脏代谢谱的差异,为有毒药物的毒性差异研究提供物质基础。方法8周C57雄性小鼠、C3H雄性小鼠、C57雌性小鼠、2周未离乳C57雄性小鼠作为研究对象,利用代谢组学相关技术结合分子生物学手段研究不同种间、性别和年龄小鼠肝脏代谢谱的差异。结果显示不同种间、性别和年龄小鼠肝脏的相关代谢通路存在差异,主要涉及氨基酸合成和代谢的相关代谢通路,同时不同种间、性别和年龄小鼠肝脏的I相和II相代谢酶的活性和mRNA基因表达存在差异,代谢酶的活性和mRNA基因表达越高,马兜铃酸I的LD50值越大,其毒性越小。结论本研究揭示了不同种间、年龄和性别小鼠肝脏代谢谱的差异,从不同种间、年龄和性别小鼠肝脏物质基础方面解释了马兜铃酸I毒性差异的原因,也为其他有毒药物的合理评价提供了数据支持。Objective To study the differences of liver metabolism spectrum among different species,sexes and ages of mice,so as to provide the material basis for the study of toxicity difference of toxic drugs by using metabolomics and other related techniques.Methods Eight-week-old C57 male,C3H male,and C57 female mice as well as 2-week-old unweaned C57 male mice were used as subjects,to study the difference of liver metabolism spectrum among different species,sexes and ages of mice by using metabonomicsrelated techniques combined with molecular biology techniques.Results The results showed that there were differences in the relevant metabolic pathways in the livers of mice of different species,sexes,and ages,which were mainly related to the metabolic pathways of amino acid synthesis and metabolism.Furthermore,there were differences in phase I and II metabolic enzyme activities and mRNA expression in the livers of mice of different species,sexes,and age.The higher the metabolic enzyme activity and mRNA expression,the larger the LD50 of AAI and the lower the toxicity of AAI.Conclusion This study revealed the differences of liver metabolism spectrum among different species,ages and genders of mice,it explained the reason of the toxicity difference of aristolochic acid I from the aspect of liver material basis of different species,age and sex mice,also provided data support for the reasonable evaluation of other toxic drugs.

关 键 词：代谢组学 毒性差异 代谢酶 

分 类 号：R978[医药卫生—药品]