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基于质谱法的雷公藤多苷诱导大鼠一般毒性相关尿液代谢谱分析

Mass spectrometry-based metabolic profiling of rat urine associated with general toxicity induced by the multiglycoside of Tripterygium wilfordii Hook. f.

作者信息

Chen Minjun, Ni Yan, Duan Hongquan, Qiu Yunping, Guo Congying, Jiao Yang, Shi Huijuan, Su Mingming, Jia Wei

机构信息

School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, People's Republic of China.

出版信息

Chem Res Toxicol. 2008 Feb;21(2):288-94. doi: 10.1021/tx7002905. Epub 2008 Jan 19.

Abstract

We propose here a combined gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) metabolic profiling strategy to elucidate the toxicity in rats induced by orally administered multiglycosides of Tripterygium wilfordii Hook. f. (GTW) in multiple organs including the kidney, liver, and testis. Overnight 12-h urine samples were collected from Sprague-Dawley male rats exposed to GTW (100 mg/kg/day, n = 6) and healthy controls ( n = 6) at predose and at the 1st, 3rd, 6th, 10th, and 14th day postdose for both GC/MS and LC/MS analyses. The integrated urinary MS data were analyzed via multivariate statistical techniques such as principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) to identify the differential metabolites and pertinent altered biological pathways in response to the herbal toxin. The liver, kidney, and testis were also assessed using conventional histopathological examinations at the end point of the experiment. This work indicates that GTW caused a time-dependent toxic effect at a high dose as revealed by the perturbed metabolic regulatory network involving disorders in energy metabolism, elevated amino acid and choline metabolism pathways, as well as altered structure of gut flora. This integrated MS-based metabolic profiling approach has been able to capture and probe the metabolic alterations associated with the onset and progression of multiorgan toxicity induced by GTW, thereby permitting a comprehensive understanding of systemic toxicity for phytochemicals and other types of xenobiotic agents.

摘要

我们在此提出一种气相色谱/质谱联用(GC/MS)和液相色谱/质谱联用(LC/MS)的代谢谱分析策略,以阐明雷公藤多苷(GTW)经口给药诱导大鼠肾脏、肝脏和睾丸等多个器官产生的毒性。从接受GTW(100 mg/kg/天,n = 6)的Sprague-Dawley雄性大鼠和健康对照(n = 6)中,在给药前以及给药后第1、3、6、10和14天收集12小时过夜尿液样本,用于GC/MS和LC/MS分析。通过主成分分析(PCA)和偏最小二乘判别分析(PLS-DA)等多元统计技术对整合后的尿液质谱数据进行分析,以识别差异代谢物以及响应草药毒素而发生改变的相关生物途径。在实验终点还使用传统组织病理学检查对肝脏、肾脏和睾丸进行评估。这项研究表明,GTW在高剂量下会产生时间依赖性毒性作用,这表现为能量代谢紊乱、氨基酸和胆碱代谢途径升高以及肠道菌群结构改变等代谢调节网络的扰动。这种基于质谱的综合代谢谱分析方法能够捕捉和探究与GTW诱导的多器官毒性的发生和发展相关的代谢变化,从而全面了解植物化学物质和其他类型的外源剂的全身毒性。

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