基于血清代谢组学的利巴韦林干预肾阳虚外感小鼠的药效或毒性作用机制研究  

Mechanism of Pharmacological or Toxicity Effect of Ribavirin on Kidney-Yang Deficiency Syndrome Mice Model Infected with Influenza Virus A Based on Serum Metabolomics

作　　者：孙启慧 李灿[1] 付业佩 杨勇[1] 蒋海强[1] 巩丽丽[1] 容蓉[1] 

机构地区：[1]山东中医药大学,济南250355

出　　处：《中国药学杂志》2017年第16期1409-1414,共6页Chinese Pharmaceutical Journal

基　　金：国家科技重大专项资助(2014ZX09509001-001);国家自然科学基金资助项目(81273626);山东省重点研发计划资助(2016CYJS08A01-5)

摘　　要：目的研究利巴韦林对肾阳虚外感小鼠血清中内源性物质变化的干预作用,寻找其潜在生物标志物,从代谢组学视角探索利巴韦林的药效或毒性作用机制。方法昆明KM小鼠随机分为正常组、模型组、利巴韦林组;采用连续15 d腹腔注射雌二醇方法复制肾阳虚模型,然后用H1N1滴鼻感染建立肾阳虚外感小鼠模型;利巴韦林组给药干预,每日1次,连续6 d,其他组分别给予等量的生理盐水。记录体重、肛温,于末次给药24 h后收集血清样本,采用高效液相色谱-飞行时间质谱(HPLCTOF/MS)检测。结果与正常组相比利巴韦林组小鼠肺指数和死亡率降低,体重、肛温也持续降低;血清样本采集的数据经处理,共鉴定出D-葡萄糖、鞘氨醇、亚油酸等14种代谢产物差异显著;药物干预后,小鼠血清中亚油酸、花生四烯酸和鞘脂代谢通路中物质出现良好的回调趋势,糖和甘油磷脂代谢相对应的部分物质出现紊乱。结论利巴韦林干预肾阳虚外感可能是通过调节亚油酸、花生四烯酸和鞘脂代谢等途径发挥药效;其毒副作用可能与糖和甘油磷脂代谢等通路紊乱有关。OBJECTIVE To analyze the endogenous metabolite changes in the sera of kidney-yang deficiency syndrome mice infected with influenza virus A after intervention by ribavirin. And to explore the mechanism of pharmacological or toxicity effect of ribavirin. METHODS KM mice were randomly divided into three groups as normal group,model group and ribavirin group. Mice were infected with virus A after fifteen days Kidney-Yang deficiency syndrome was established. Ribavirin group were orally administrated with ribavirin for 6 consecutive days after inoculation,and the other two groups were given with equal volume of saline solution in the same way. Body weight,rectal temperature were recorded daily. Serum samples were collected from mouse 24 h after the last administration for HPLC-TOF/MS analysis. RESULTS The results show that ribavirin has good therapeutic effects on the lung index and high mortality rate of mice model. Compared with normal and model groups,the body weight and rectal temperature of them performed falling continuously. The LC-MS data were analyzed with multivariate statistical analysis and 14 potential metabolic markers were obtained which contained D-glucose,sphinganine,linoleic acid and so on. In ribavirin group,metabolism of linoleic acid,arachidonic acid and sphinganine appeared the trend of normal. And sugar and glycerophospholipid became disorders. CONCLUSION The metabolomics study and pharmacological experiment show that ribavirin might play a role of efficacy in a way that has close correlation with the linoleic acid,arachidonic acid and sphingolipid metabolic pathways. And the toxicity effect may be related to sugar and glycerophospholipid metabolic pathways.

关 键 词：代谢组学 利巴韦林 肾阳虚外感 生物标志物 

分 类 号：R965[医药卫生—药理学]