Lv Haitao, Liu Lian, Zhang Yingzhi, Song Ting, Lu Juan, Chen Xi
Department of Medicine, Albert Einstein College of Medicine, New York, USA.
Mol Biosyst. 2010 Oct;6(10):2056-67. doi: 10.1039/c0mb00064g. Epub 2010 Aug 11.
We introduce the use of Ingenuity Pathway Analysis to analyzing global metabonomics in order to characterize phenotypically biochemical perturbations and the potential mechanisms of the gentamicin-induced toxicity in multiple organs. A single dose of gentamicin was administered to Sprague Dawley rats (200 mg/kg, n = 6) and urine samples were collected at -24-0 h pre-dosage, 0-24, 24-48, 48-72 and 72-96 h post-dosage of gentamicin. The urine metabonomics analysis was performed by UPLC/MS, and the mass spectra signals of the detected metabolites were systematically deconvoluted and analyzed by pattern recognition analyses (Heatmap, PCA and PLS-DA), revealing a time-dependency of the biochemical perturbations induced by gentamicin toxicity. As result, the holistic metabolome change induced by gentamicin toxicity in the animal's organisms was characterized. Several metabolites involved in amino acid metabolism were identified in urine, and it was confirmed that gentamicin biochemical perturbations can be foreseen from these biomarkers. Notoriously, it was found that gentamicin induced toxicity in multiple organs system in the laboratory rats. The proof-of-knowledge based Ingenuity Pathway Analysis revealed gentamicin induced liver and heart toxicity, along with the previously known toxicity in kidney. The metabolites creatine, nicotinic acid, prostaglandin E2, and cholic acid were identified and validated as phenotypic biomarkers of gentamicin induced toxicity. Altogether, the significance of the use of metabonomics analyses in the assessment of drug toxicity is highlighted once more; furthermore, this work demonstrated the powerful predictive potential of the Ingenuity Pathway Analysis to study of drug toxicity and its valuable complementation for metabonomics based assessment of the drug toxicity.
我们引入了通路分析软件（Ingenuity Pathway Analysis）来分析整体代谢组学，以表征庆大霉素诱导的多器官毒性的表型生化扰动及其潜在机制。给斯普拉格-道利大鼠单次注射庆大霉素（200 mg/kg，n = 6），并在给药前-24 - 0小时、给药后0 - 24、24 - 48、48 - 72和72 - 96小时收集尿液样本。通过超高效液相色谱/质谱联用仪（UPLC/MS）进行尿液代谢组学分析，并通过模式识别分析（热图、主成分分析和偏最小二乘判别分析）对检测到的代谢物的质谱信号进行系统解卷积和分析，揭示了庆大霉素毒性诱导的生化扰动的时间依赖性。结果，表征了庆大霉素毒性在动物机体中引起的整体代谢组变化。在尿液中鉴定出了几种参与氨基酸代谢的代谢物，并证实从这些生物标志物可以预测庆大霉素的生化扰动。值得注意的是，发现在实验大鼠中庆大霉素会诱导多器官系统毒性。基于知识的通路分析软件（Ingenuity Pathway Analysis）显示，庆大霉素会诱导肝脏和心脏毒性，以及先前已知的肾脏毒性。肌酸、烟酸、前列腺素E2和胆酸等代谢物被鉴定并验证为庆大霉素诱导毒性的表型生物标志物。总之，再次强调了代谢组学分析在药物毒性评估中的重要性；此外，这项工作证明了通路分析软件（Ingenuity Pathway Analysis）在研究药物毒性方面具有强大的预测潜力，以及其对基于代谢组学的药物毒性评估的宝贵补充作用。
