采用GC-MS代谢组学技术表征阿司咪唑诱导斑马鱼心脏毒性的内源性代谢物

发布时间：2018-09-03 14:16

【摘要】：目的分析阿司咪唑诱导斑马鱼心脏毒性后内源性代谢物的变化特点,寻找与心脏毒性发生相关的代谢生物标志物。方法采用阿司咪唑处理发育48hpf(hours post fertilization)斑马鱼幼鱼,观察其心率、静脉窦(sinus venous,SV)-动脉球(bulbus arteriosus,BA)距离、心脏形态等毒性改变,同时采集斑马鱼组织进行气相色谱-质谱联用法代谢组学分析并寻找生物标志物。结果阿司咪唑处理斑马鱼幼鱼后,心率降低(P0.05),出现明显的房室传导阻滞,心脏形态改变,表现出典型的心脏毒性,且呈剂量依赖性。代谢组学分析结果显示,阿司咪唑处理组的代谢轮廓与对照组明显不同,斑马鱼体内葡萄糖、甘氨酸、乳酸肌肝、谷氨酰胺、N-乙酰-L-赖氨酸、L-脯氨酸、柠檬酸、L-酪氨酸、磷酸、胆固醇、棕榈酸等12种代谢物发生了显著变化。结论这些结果显示,基于新型模式生物斑马鱼的代谢组学技术可以用于表征药物引起的心脏毒性改变,找到的一些与心脏毒性相关的潜在生物标志物将有助于药源性心脏毒性的早期预测和评价。
[Abstract]:Objective to analyze the changes of endogenous metabolites in zebrafish induced by azimidazole and to find the metabolic biomarkers associated with cardiac toxicity. Methods the developmental 48hpf (hours post fertilization) zebrafish were treated with azimidazole. The heart rate, the distance between venous sinus (sinus venous,SV) and arterial ball (bulbus arteriosus,BA), and the morphology of the heart were observed. The zebrafish tissues were collected and analyzed by gas chromatography-mass spectrometry (GC-MS) to find biomarkers. Results after treated with azimidazole, the heart rate of juvenile zebrafish decreased (P0.05), the atrioventricular block appeared, the heart shape changed, and showed the typical cardiac toxicity, which was dose-dependent. The results of metabolomics analysis showed that the profile of metabolism in the azimidazole treated group was obviously different from that in the control group, and that in zebrafish, glucose, glycine, lactate muscle liver, glutamine N-acetyl-L-lysine L-proline, citrate L-tyrosine, phosphoric acid, Cholesterol, palmitic acid and other 12 metabolites changed significantly. Conclusion these results suggest that metabonomics based on new model biological zebrafish can be used to characterize drug-induced cardiac toxicity changes. Some potential biomarkers associated with cardiac toxicity will contribute to early prediction and evaluation of drug-induced cardiac toxicity.
【作者单位】：山东省科学院生物研究所山东省生物传感器重点实验室;山东大学齐鲁医院药剂科;山东省科学院生物研究所山东省生物传感器重点实验室;
【基金】：国家自然科学基金青年项目(81202584) 山东省中医药科学技术研究项目(2013-173) 甘肃省中医药科学技术研究课题(GZK-2012-56)
【分类号】：R96

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