Z24经口染毒大鼠血浆的代谢组学研究

Study of metabonomic profile of plasma from rats administrated orally with Z24

目的 研究Z2 4染毒大鼠血浆的代谢表型改变及其与组织病理和血液生化指标的相关性 ,探讨代谢组学在药物毒性早期筛选中的应用。方法 Wistar大鼠连续经口染毒 0、60、13 0和 2 0 0mg/kgZ2 45d后收集血浆 ,测定1 HNMR谱 ,并进行血浆生化指标测定和肝脏组织病理学检查。结果 2 0 0mg/kg组大鼠血浆丙氨酸转氨酶 (ALT)、天冬氨酸转氨酶 (AST)及总胆红素 (TbiL)分别升高了 14 8 4%、14 0 %和 10 9 8% ;13 0和 2 0 0mg/kg组均出现不同程度的肝脏炎症和坏死。血浆1 HNMR谱偏最小乘方分析 (PLS DA)发现在不同染毒条件下 ,各组动物的代谢谱各不相同 ,与肝脏病理和血浆生化改变相一致 ,并且其敏感性优于常规毒理学检测指标。结论 大鼠血浆1 HNMR代谢谱与Z2 4毒作用强度密切相关 。

Objective to study the effects of Z24 on the metabonomic profile of rat plasma and its relationship with blood biochemical indicators and histopathology,explore the feasibility of metabonomics in the application of early toxicity screening of drug candidate.Methods 20 femal Wistar rats were administrated orally with 0,60,130 and 200 mg/kg Z24 for 5 days respectively.After dosing, plasma was collected and its 1H nuclear magnetic resonance(NMR) spectra were acquired and all animals were taken blood biochemical analysis and liver histopathology examination.Results The plasma alanine aminotransferase(ALT),aspartate transaminase(AST),total bilirubin(Tbil) level of 200 mg/kg group rats were increased by 148.4%, 140% and 109.8% compared to controls respectively. There were clear necrosis foci in liver histopathology of 200 mg/kg and 130 mg/kg groups. And the plasma metabonomic approach could readily distinguish the Z24 dosed toxicity, with a good agreement between clinical chemistry, microscopically examination and partial-least-squares discriminant analysis(PLS-DA) data. And PLS-DA analysis suggested effects at low doses, which were not as evident by clinical chemistry or microscopic analysis.Conclusion The effect of Z24 on the rat plasma metabonomic profile is related with Z24 toxicology which supports the contention that the metabonomic approach represents a promising new technology for the development of a rapid throughput in vivo toxicity screening tool.