偕胺肟小分子化合物铀促排作用及其代谢组学  

Uranium Decorporation and Metabolomic Study of Small Molecular Compounds of Amidoxime

作　　者：朱金寿 黄荣清 李志恒 肖炳坤 缪潇瑶 杨芳[1] ZHU Jin-shou;HUANG Rong-qing;LI Zhi-heng;XIAO Bing-kun;MIAO Xiao-yao;YANG Fang(Department of Pharmacy,Academy of Military Medicine,Qinghai University,Xining 810016,China;Academy of Military Medicine,Beijing 100850,China)

机构地区：[1]青海大学医学院药学系,西宁810016 [2]军事医学研究院,北京100850

出　　处：《科学技术与工程》2025年第7期2741-2747,共7页Science Technology and Engineering

摘　　要：采用肟化加成反应合成一种新偕胺肟小分子化合物并进行铀促排作用评价,结合代谢组学方法探讨在动物体内促排时引起的内源性代谢物的变化,寻找与之相关的差异性代谢物并探索其代谢通路及作用机制。将小鼠分为空白组(NG)、模型组(MG)、0.42 mmol/kg新促排灵组(ZnNa_(3)-DTPA,YG)、0.21 mmol/kg偕胺肟组(CN)及0.42 mmol/kg偕胺肟组(EN),尾静脉注射醋酸铀酰后立即尾静脉注射阳性药(ZnNa_(3)-DTPA)和偕胺肟化合物,给药24 h后通过电感耦合等离子体质谱仪(inductively-coupled plasma mass spectrometer,ICP-MS)测定小鼠肾和股骨中铀含量。采用GC-MS(gas chromatograaphy-mass spectrometer)对各组小鼠血清中代谢物进行鉴定,应用正交偏最小二乘判别分析方法(orthogonal partial least squares discriminant analysis,OPLS-DA),通过变量投影重要性值(variable importance in the projection,VIP)>1结果筛选为潜在差异性代谢物,应用质谱数据库并通过MetaboAnalyst平台分析差异性代谢产物及其相关通路。结果表明与模型组相比0.42 mmol/kg偕胺肟化合物组分别减少肾、股骨内61.70%、54.74%铀含量;同剂量的阳性组减少肾、股骨内铀含量分别为60.70%、40%。表明偕胺肟小分子化合物具有铀促排作用。代谢组学分析显示偕胺肟组代谢轮廓与模型组明显分离,与阳性组相比更接近正常组,筛选共发现14个差异性代谢物,代谢通路富集分析后显示与之相关的代谢通路主要为酪氨酸代谢;苯丙氨酸、酪氨酸、色氨酸的生物合成及甘氨酸、丝氨酸、苏氨酸代谢等。小分子偕胺肟化合物具有铀促排效果,且优于ZnNa_(3)-DTPA,并对铀所致肾损伤具有保护作用。A new amidoxime small molecule compound was synthesized by oximation addition reaction and the uranium decorporation was evaluated.The changes of endogenous metabolites caused by Uranium decorporation in animals were investigated by metabonomics method,and the related differential metabolites were searched for and their metabolic pathways and mechanisms were explored.The mice were divided into blank group(NG),model group(MG),0.42 mmol/kg ZnNa_(3)-DTPA group(YG),0.21 mmol/kg amidoxime group(CN)and 0.42 mmol/kg amidoxime group(EN),and were injected with positive drug(ZnNa_(3)-DTPA)and amidoxime compounds in tail vein immediately after the tail vein injection of uranyl acetate and amidoxme compound,the uranium content in the kidney and femur of mice was determined by Inductively-coupled plasma mass spectrometer(ICP-MS)24 h later.The metabolites in the serum of each group were identified by GC-MS(gas chromatograaphy-mss spectrometer),and screened as potentially differentiated metabolites by orthogonal partial least squares discriminant analysis(OPLS-DA)with variable importance in the projection(VIP)>1,mass spectrometry database and MetaboAnalyst platform were used to analyze the differential metabolites and their associated pathways.The results show that compared with model group,0.42 mmol/kg amidoxime compound group decreased uranium content in kidney and femur by 61.70%and 54.74%,and the positive group at the same dose reduced the uranium content in kidney and femur by 60.70%and 40%,respectively.The results indicated that the small molecule compound of aminoxime had significant uranium decorporation.Metabolomic analysis showed that the metabolic profile of the amidoxime group was significantly different from that of the model group,which was closer to that of the normal group than that of the positive group.A total of 14 different metabolites were found after screening,and the enrichment analysis of metabolic pathways showed that the metabolic pathways related to them were mainly tyrosine metabolism.Biosynthesis of

关 键 词：偕胺肟化合物 合成 铀促排 气相色谱-质谱联用 代谢组学 

分 类 号：R917[医药卫生—药物分析学]