东莨菪碱中毒大鼠的代谢组学

Metabonomics of Scopolamine Intoxication in Rats

目的研究东莨菪碱中毒大鼠体内差异代谢物及代谢通路与毒性的关系。方法40只Sprague-Dawley(SD)大鼠分为对照组和3个不同剂量给药组,连续给药30 d建立长期中毒模型,应用气相色谱-质谱(GC/MSD)联用技术,结合多元变量分析和数据库检索,对不同组别大鼠血清和尿液中内源性代谢物进行分析,筛选鉴定潜在的差异代谢物;通过代谢分析(MetaboAnalyst)软件进行代谢通路富集;并将各组大鼠脏器组织制作石蜡切片,HE染色后显微镜观察。结果与对照组大鼠相比较,给药组大鼠的代谢轮廓,差异有统计学意义(P<0.05);给药组血清及尿液中共筛选出谷氨基酸、甘氨酸、脯氨酸、肌氨酸、丙氨酸等17种差异代谢物,主要涉及丙氨酸-天门冬氨酸-谷氨酸代谢,甘氨酸-丝氨酸-苏氨酸代谢,谷氨酰胺-谷氨酸代谢等9条代谢通路;病理学检验主要以神经细胞变性为主。结论东莨菪碱的毒性作用主要表现为神经毒性,其毒性作用可能与其扰乱丙氨酸-天门冬氨酸-谷氨酸代谢、甘氨酸-丝氨酸-苏氨酸代谢、谷氨酰胺-谷氨酸代谢有关。

Objective To study the relationship between different metabolites,metabolic pathways and toxicity in scopolamine intoxicated rats.Methods 40 Sprague-Dawley(SD)rats were divided into control group and 3 groups with different doses of drugs.Chronic intoxication model was established after continuous administration for 30 days.By using Gas chromatography-mass spectrometry(GC/MSD),and multivariate analysis and database retrieval,endogenous metabolites in serum and urine of different groups of rats were analyzed to screen and identify potential differential metabolites.Metabolic pathway enrichment was carried out by MetaboAnalyst software.The paraffin sections were stained with HE and observed microscopically.Results The metabolic profile of the control group and the administration group was significantly different(P<0.05).In the serum and urine samples of the drug administration groups,17 different metabolites,including glutamic acid,glycine,proline,creatine and alanine,were screened out,mainly involving 9 metabolic pathways,including alanine-aspartate-glutamic acid metabolism,glycine-serine-threonine metabolism,and glutamine-glutamic acid metabolism,etc.The main pathological result was neurodegeneration.Conclusion The toxic effect of scopolamine is mainly neurotoxicity,and its mechanism of toxicity may be related to its disturbance of alanine-aspartic acid-glutamic acid metabolism,glycine-serinethreonine metabolism,glutamine-glutamic acid metabolism.