Z24经口染毒大鼠尿液的核磁共振谱代谢组学研究

A nuclear magnetic resonance spectroscopic metabonomics analysis for urine from rats administrated Z24 orally

目的 研究Z2 4染毒大鼠尿液代谢组学的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大鼠连续经口给予Z2 4 6 0 ,130及 2 0 0mg·kg- 1,连续 5d后收集 2 4h尿液 ,测定核磁共振([1H]NMR)谱 ,并进行血浆生化指标测定和肝脏组织病理学检查。结果 Z2 4 2 0 0mg·kg- 1组大鼠血浆谷丙转氨酶、谷草转氨酶和总胆红素分别升高14 8% ,14 0 %和 110 % ;130和 2 0 0mg·kg- 1组均有不同程度的肝脏炎症和坏死。 [1H]NMR谱主成分分析发现各组在不同染毒条件下的代谢状态可相互区分 ,与肝脏病理和血浆生化改变相一致。结论 大鼠尿液 [1H]NMR代谢谱与Z2 4毒性作用强度密切相关 ,代谢组学分析是一种有良好发展前景的体内药物毒性早期筛选的方法。

AIM To study effects of Z24 on the metabon om ics profile of rat urine and its relationship with blood biochemical indices and histopathology,explore the easibility of metabonomics in the application of ear ly toxicity screening of drug candidate. METHODS Twenty femal Wista r rats were administrated orally with 60, 130 and 200 mg·kg -1 Z24 for 5 d, respectively. After dosing, 24 h urine was collected and its [ 1H]NMR spectra were acquired, and subjected to data process and principal comp onents analyses (PCA). On d 7, all animals were taken blood for biochemical anal ysis and liver histopathology examination. RESULTS The plasma G PT, GOT, total bilirubin(TBIL) level of 200 mg·kg -1 group rats were incre a sed by 148%, 140% and 110% as compared to controls, respectively. There were cle ar necrosis foci in liver histopathology of 200 and 130 mg·kg -1 groups. And the urine metabonomics approach could readily distinguish the Z24 toxicity, with a good agreement between clinical chemistry, microscopical exami nation and PCA data. And PCA analysis suggested effects at low doses, wh ich were not as evident by clinical chemistry or microscopic analysis. CON CLUSION The effect of Z24 on the rat urine metabonomics profile is relate d to Z24 toxicology which supports the contention that the metabonomics approa ch represents a promising new technology for the development of a rapid througho ut in vivo toxicity screening fool.