异烟肼肝毒性的代谢组学特征研究

Metabonomics of isoniazid in rats' liver tissues

目的:研究大鼠灌胃异烟肼后其尿液的代谢表型改变及其与组织病理学和血浆生化指标变化的相关性,探讨代谢组学在药物毒理学研究中的应用。方法:Wistar大鼠连续灌胃0,25,50,100,200和400 mg.kg-1异烟肼14 d后收集尿样,测定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:常规毒理学评价方法发现大鼠在中、高剂量表现明显的肝毒性;给药组尿样1H-NMR谱2-氨基己二酸、葡萄糖和牛磺酸明显增加,2-酮戊二酸和柠檬酸明显降低。各剂量组的代谢产物谱变化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:大鼠尿液1H-NMR代谢产物谱与异烟肼毒性作用强度密切相关,异烟肼引起的肝毒性与线粒体功能受损及三羧酸循环中能量代谢异常有关,还与葡萄糖代谢紊乱有关。代谢组学分析在毒理学研究中有着广泛的应用前景。

Objective： To study whether isoniazid （INH） impacts the metabonomic profile of rat urine as well as blood biochemical and histopathological outcomes. Methods： 24 male Wistar rats were orally administrated with INH 0, 25, 50, 100, 200 or 400 mg·kg^-1 for 14 days, respectively. Subsequently, the urinary samples of rats were collected to measure metabonomic spectra by ^1 H nuclear magnetic resonance（ NMR） technique. The analysis of blood samples and liver tissues was used to correlate the status of blood biochemical and histopathological outcomes to the urinary metabomics. Results： INH at moderate and higher dosage was found to cause the rats＇ hepatotoxicity. Escalations of concentrations of urinary taurine, 2-aminoadipate and glucose as well as reductions of concentrations of urinary citrate and 2-oxoglutarate were found by analysis of the ^1H-NMR spectra in INH-treated rats. The outcomes of blood biochemical and histopathological tests were coincident with the analysis of urinary metabonomic spectra by ^1 H-NMR technique. The metabonomic analysis was more sensitive than the traditional toxic evaluation as a potential tool of toxicological investigations. Conclusion ： The abnormality of the urinary metabomic spectra was closely associated with the INH-induced hepatic toxicity, which manifested the mitochondrial dysfunctions and abnormal energy metabolism in TCA cycle as well as the abnormal glucose metabolism.