【摘要】：目的分析阿司咪唑誘導(dǎo)斑馬魚心臟毒性后內(nèi)源性代謝物的變化特點,尋找與心臟毒性發(fā)生相關(guān)的代謝生物標(biāo)志物。方法采用阿司咪唑處理發(fā)育48hpf(hours post fertilization)斑馬魚幼魚,觀察其心率、靜脈竇(sinus venous,SV)-動脈球(bulbus arteriosus,BA)距離、心臟形態(tài)等毒性改變,同時采集斑馬魚組織進(jìn)行氣相色譜-質(zhì)譜聯(lián)用法代謝組學(xué)分析并尋找生物標(biāo)志物。結(jié)果阿司咪唑處理斑馬魚幼魚后,心率降低(P0.05),出現(xiàn)明顯的房室傳導(dǎo)阻滯,心臟形態(tài)改變,表現(xiàn)出典型的心臟毒性,且呈劑量依賴性。代謝組學(xué)分析結(jié)果顯示,阿司咪唑處理組的代謝輪廓與對照組明顯不同,斑馬魚體內(nèi)葡萄糖、甘氨酸、乳酸肌肝、谷氨酰胺、N-乙酰-L-賴氨酸、L-脯氨酸、檸檬酸、L-酪氨酸、磷酸、膽固醇、棕櫚酸等12種代謝物發(fā)生了顯著變化。結(jié)論這些結(jié)果顯示,基于新型模式生物斑馬魚的代謝組學(xué)技術(shù)可以用于表征藥物引起的心臟毒性改變,找到的一些與心臟毒性相關(guān)的潛在生物標(biāo)志物將有助于藥源性心臟毒性的早期預(yù)測和評價。
[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.
【作者單位】： 山東省科學(xué)院生物研究所 山東省生物傳感器重點實驗室;山東大學(xué)齊魯醫(yī)院藥劑科;山東省科學(xué)院生物研究 所山東省生物傳感器重點實驗室;
【基金】：國家自然科學(xué)基金青年項目(81202584) 山東省中醫(yī)藥科學(xué)技術(shù)研究項目(2013-173) 甘肅省中醫(yī)藥科學(xué)技術(shù)研究課題(GZK-2012-56)
【分類號】：R96

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