• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

GC/TOF-MS代谢组学技术研究雷公藤甲素在大鼠体内的急性毒性

邵凤, 刘林生, 阿基业

邵凤, 刘林生, 阿基业. GC/TOF-MS代谢组学技术研究雷公藤甲素在大鼠体内的急性毒性[J]. 中国药科大学学报, 2014, 45(6): 703-709. DOI: 10.11665/j.issn.1000-5048.20140616
引用本文: 邵凤, 刘林生, 阿基业. GC/TOF-MS代谢组学技术研究雷公藤甲素在大鼠体内的急性毒性[J]. 中国药科大学学报, 2014, 45(6): 703-709. DOI: 10.11665/j.issn.1000-5048.20140616
shu
SHAO Feng, LIU Linsheng, A Jiye. Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluate acute toxicity of triptolide in rats[J]. Journal of China Pharmaceutical University, 2014, 45(6): 703-709. DOI: 10.11665/j.issn.1000-5048.20140616
Citation: SHAO Feng, LIU Linsheng, A Jiye. Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluate acute toxicity of triptolide in rats[J]. Journal of China Pharmaceutical University, 2014, 45(6): 703-709. DOI: 10.11665/j.issn.1000-5048.20140616
shu

GC/TOF-MS代谢组学技术研究雷公藤甲素在大鼠体内的急性毒性

  • 1.

    南京医科大学第一附属医院Ⅰ期临床研究室

  • 2.

    中国药科大学药物代谢动力学重点实验室，药物分子设计与成药性优化重点实验室

  • 3.

    苏州大学附属第一医院药学部

基金项目: 国家自然科学基金面上项目资助(No.30572228)；国家“重大新药创制”科技重大专项资助项目(No.2011ZX09302-003-02)；江苏省药物代谢动力学重点实验室项目资助(No.BM2012012)；江苏省科技重大专项资助项目(No.BM2011017)

Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluate acute toxicity of triptolide in rats

摘要

    摘要
  • 摘要: 采用GC/TOF-MS代谢组学技术研究雷公藤甲素对大鼠尿液中内源性小分子化合物的影响和毒性作用机制，寻找与毒性相关标志物，为雷公藤类药物临床毒性的早期预防和诊断提供依据。SD大鼠随机分为4组，分别为雷公藤甲素高(2.4 mg/kg)、中(1.2 mg/kg)、低(0.6 mg/kg)剂量组及空白对照组。单次灌胃给药后，收集第0、1、3和7天的尿液，GC/TOF-MS进行分析，对尿液中内源性小分子化合物进行鉴定并获取半定量数据，经过主成分分析发现:不同剂量给药和不同时间取样尿液中内源性小分子代谢谱有明显差异，可被清晰区分并呈明显的动态变化轨迹。代谢组学数据分析结果与常规血液生化和组织病理学检查结果基本吻合。研究结果发现，给药引起尿液中的苹果酸、枸橼酸、牛磺酸、谷氨酸、苏氨酸及软脂酸等发生明显改变，提示与雷公藤甲素毒性相关，为潜在的毒性标志物。本研究结果表明，通过测定尿液中小分子代谢物可反映雷公藤甲素对大鼠的毒性，代谢组学技术可以作为药物毒性评价方法。代谢通路分析结果提示，雷公藤甲素对肝脏的毒性机制可能与大鼠肝脏线粒体受损、影响三羧酸循环、氨基酸代谢及脂质代谢有关。
    Abstract: To evaluate toxicity in rats after orally giving triptolide by using the gas chromatography time-of-flight mass spectrometry(GC/TOF-MS)based metabolomics approach. Potential biomarkers identified here paved a way to new implications of clinical early prevention and diagnosis of safety. In this study, SD rats were randomly divided into four groups, that included high dose(2. 4 mg/kg), medium dose(1. 2 mg/kg), low dose(0. 6 mg/kg)and control groups, respectively. Following by single orally dosing, urine, serum and tissue sample were collected, respectively on day 0, day 1, day 3 and day 7 for a subsequent metabolomic bioanalysis. Multivariate data analysis was then used to process the data which indicated excellent separation between different doses and treatment days. The metabolic pattern after treatment with triptolide at high and medium dose visually depicted the occurrence, development and recovery process of toxicity that vividly demonstrated dose and time-dependent toxicity following different dose of triptolide in rats. Metabolomic results were consistent with those obtained from the routine biochemical assays and histopathological characterization. The results indicated that malate, citrate, taurine, glutamate, threonine and stearic acid, etc. could serve as potential toxicity biomarkers. Our study indicated that a metabolomic method established in this study provided a promising and effective approach to evaluate the mechanism of toxicity and the mechanism of hepatotoxicity was related with the impairment mitochondria, tricarboxylic acid cycle, amino acids and free fatty acids metabolism.
    • HTML全文
    • 参考文献(16)
  • [1] Bouhifd M,Hartung T,Hogberg HT,et al.Review:toxicometabolomics[J].J Appl Toxicol,2013,33(12):1 365-1 383.
    [2] Chen M, Zhou K, Chen X, et al. Metabolomic analysis reveals metabolic changes caused by bisphenol A in rats[J].Toxicol Sci,2014,138(2):256-267.
    [3] Liang YJ,Wang HP,Long DX,et al.Applyingbiofluidmetabonomic techniques to analyze the combined subchronic toxicity of propoxur and permethrin in rats [J].Bioanalysis,2012,4(24):2 897-2 907.
    [4] Mattes W,Davis K,Fabian E,et al.Detection of hepatotoxicity potential with metabolite(metabolomics)profiling of rat plasma[J].Toxicol Lett,2014,230(3):467-478.
    [5] Yu J,Jiang YS,Jiang Y,et al.Targeted metabolomic study indicating glycyrrhizin′s protection against acetaminophen-induced liver damage through reversing fatty acid metabolism[J].Phytother Res,2014,28(6):933-936.
    [6] Wang L,Wang C,Zhao YD.Pharmacological effects of triptolide progress[J].J TCM Univ Hunan(湖南中医药大学学报),2010,30(2):37-39.
    [7] Hu PY,Li ZL,Pu SB,et al.Research Advances on triptreygiumwilfordii[J].Chin Wild Plant Resour(中国野生植物资源),2013,32(2):1-3.
    [8] Shui GX,Wan YG,Jiang CM.Progress in tripterygiumwilfordii and its bioactive components in the field of pharmacodynamics and pharmacology[J].China J Chin Mater Med(中国中药杂志),2010,35(4):515-520.
    [9] A JY,Huang Q,Wang G,et al.Global analysis of metabolites in rat and human urine based on gas chromatography/time-of-flight mass spectrometry[J].Anal Biochem,2008,379(1):20-26.
    [10] A JY,Shao F,Wang G,et al.Gas chromatography time-of-flight/mass spectrometry based metabolomic approach to evaluating toxicity of triptolide [J].Metabolomics,2011,7(2):217-225.
    [11] Gullberg J,Jonsson P,Nordstrom A,et al.Design of experiments:an efficient strategy to identify factors influencing extraction and derivatization of Arabidopsis thaliana samples in metabolomic studies with gas chromatography/mass spectrometry [J].Anal Biochem,2004,331(2):283-295.
    [12] Sanins SM,Nicholson JK,Elcombe C,et al.Hepatotoxin-induced hypertaurinuria:a proton NMR study [J].Arch Toxicol,1990,64(5):407-411.
    [13] Waterfield CJ, Turton JA, Scales MD, et al. The correlation between urinary and liver taurine levels and between pre-dose urinary taurine and liver damage[J].Toxicology,1993,77(1/2):1-5.
    [14] Eghbal MA,Taziki S,Sattari MR,et al.Mechanisms of phenytoin-induced toxicity in freshly isolated rat hepatocytes and the protective effects of taurine and/or melatonin[J].J Biochem Mol Toxicol,2014,28(3):111-118.
    [15] Begriche K,Massart J,Robin MA,et al.Drug-induced toxicity on mitochondria and lipid metabolism:mechanistic diversity and deleterious consequences for the liver[J].J Hepatol,2011,54(4):773-794.
    [16] Boudonck KJ,Mitchell MW,Nemet L,et al.Discovery of metabolomics biomarkers for early detection of nephrotoxicity[J].Toxicol Pathol,2009,37(3):280-292.
    • 相关文章
    • 施引文献
    • 资源附件(0)
计量
  • 文章访问数:  1416
  • HTML全文浏览量:  0
  • PDF下载量:  1136
  • 被引次数: 0
出版历程
  • 刊出日期:  2014-12-24

目录

摘要
HTML全文
    参考文献(16)
    相关文章
    施引文献
    资源附件(0)

    /

    返回文章
    返回

    版权所有：《中国药科大学学报》编辑部苏ICP备05007142号

    地址：江苏省南京市鼓楼区童家巷24号（210009）电话: 025-83271566E-mail: xuebao@cpu.edu.cn

    本系统由 北京仁和汇智信息技术有限公司 开发  百度统计

    访问量：315790

    x 关闭 永久关闭