目的 探索异补骨脂素肝毒性作用机制.方法 SD大鼠随机分为对照组和60 mg/kg异补骨脂素组,每组6只,灌胃给药,1次/d,连续7 d.给药结束后取血清检测血清生化;剖取肝和肾称重并计算脏器系数;核磁共振(NMR)进行肝代谢组检测;用Agilent Rat 4 X 44K基因表达谱芯片进行表达谱检测.结果 异补骨脂素灌胃给药7 d,大鼠的肝脏系数和肾脏系数明显增高;血清中丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的水平明显升高;显著差异代谢物8个;显著差异表达基因695个;富集分析结果主要与胆汁分泌、ABC转运体和谷胱甘肽代谢相关.Nech1、Hmgcr1、Sqle、Lss、Cyp51、Msmo1、Tm7sf2、Cyp7a1、ABCG2 和 Sult2a1 明显下调,GST 家族成员(GSTM1、GSTM2、GSTM3、GSTA3、GSTA4、GSTA5、GSTT3)明显上调.结论 60 mg/kg异补骨脂素灌胃给药7 d对大鼠具有潜在肝损伤风险.异补骨脂素肝毒性机制可能与扰乱胆汁酸分泌和谷胱甘肽代谢有关.
Study on the mechanism of isopsoralen-induced liver injury based on metabonomics and gene expression profile of liver in rats
Objective To explore the hepatotoxic mechanism of isopsoralen.Methods SD rats were randomly divided into control group and 60 mg/kg isopsoralen group.Rats were administered intragastrically once a day for 7 days.Blood was collected to detect serum biochemical indices.Livers and kidneys were weighed and their organ coefficients were calculated.Liver samples were prepared and detected for metabonomics by NMR.Total RNA was extracted from liver samples,and then,cDNA gene expression profiles were analysed.Results Liver coefficient and kidney coefficient significantly increased,meanwhile,ALT and AST significantly increased after intragastric administration of isopsoralen for 7 days.There were 8 significantly different metabolites and 695 significantly differentially expressed genes.GO and KEGG result showed that bile secretion,ABC transporters and glutathione metabolism were relevant.Nech1,Hmgcr1,Sqle,Lss,Cyp51,Msmo1,Tm7sf2,Cyp7a1,ABCG2,and Sult2a1 were down-regulated significantly,while GSTs were up-regulated significantly.Conclusion Intragastric administration of isopsoralen for 7 days was a risk of liver injury in rats.The mechanism may be related to the disturbance of bile acid secretion and glutathione metabolism.
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