雷荣辉1, 2,王青秀2, 5,颜贤忠4,吴纯启2,廖明阳2,肖小河3,王全军2*.利用1H-NMR技术研究大黄素染毒后大鼠内源性代谢物的改变[J].药物评价研究,2015,38():32-38
利用1H-NMR技术研究大黄素染毒后大鼠内源性代谢物的改变
Changes of endogenous metabolites in rats administered with emodin by 1H-NMR technology
投稿时间:2014-09-28  
DOI:
中文关键词:  大黄素;肾毒性;代谢组学;生物标志物
英文关键词:emodin; nephrotoxicity; metabonomics; biomarker
基金项目:重大新药创制科技重大专项(2013ZX09302303,2012ZX09301-001-008)
作者单位
雷荣辉1, 2,王青秀2, 5,颜贤忠4,吴纯启2,廖明阳2,肖小河3,王全军2* 1. 西安交通大学医学部公共卫生学院,陕西 西安 710061;2. 军事医学科医学院毒物药物研究所,抗毒药物与毒理学国家重点实验室(军事医学科学院),国家北京药物安全评价研究中心,北京 10085;3. 解放军302医院全军中药研究所,北京 100039;4. 国家生物医学分析中心,北京 10085;5. 北京市海淀区卫生局卫生监督所,北京 100037 
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中文摘要:
      目的 采用1H NMR的代谢组学技术揭示大黄素的肾毒性机制,寻找肾脏损害的早期生物标志物。方法 雄性SD大鼠20只,随机分为溶剂对照,大黄素170、500、1 500 mg/(kg?d)3个剂量组,连续给药16 d,给药结束后收集24 h尿液,血浆及肾组织,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 1 500 mg/(kg?d)大黄素服用16 d可引起大鼠血肌酐下降,大黄素可导致肾细胞胞浆中出现明显的空泡化改变。代谢成分的改变主要表现为血液中乳酸、糖氨基酸和脂肪酸成分下降;尿液中乳酸、糖和氨基酸成分增加;肾脏组织中醋酸盐和肌酐/肌酸明显升高,乳酸和胆碱/磷酸卵磷脂水平下降,饱和与不饱和脂肪酸及磷脂的成分比例明显改变。结论 代谢组学分析在识别药物诱导代谢成分改变方面较传统技术更灵敏;脂肪和能量代谢紊乱参与了大黄素的肾毒性,尿液中氨基酸、葡萄糖氧化三甲胺(TMAO)及肌酐可作为大黄诱导肾组织损害的潜在生物标志物。
英文摘要:
      Objective To reveal the mechanism of nephrotoxicity of emodin using 1H-NMR spectroscopy and to screen the potential biomarker of renal injury. Methods In this study, the biochemical constituents of urine, serum, and kidney tissue extracts of rats treated with emodin at different doses (0, 170, 500, and 1, 500 mg/kg/d for 16d, i.g.)were investigated using 1H-NMR techniques and pattern recognition method (PCA/PLS). Serum biochemical analysis and histopathological examination of kidney of all rats were simultaneously performed. Results Emodin (1 500 mg/kg/d) induced slight renal proximal tubule vacuolar degeneration in rats treated for 16d, while serum biochemical indexes were not affected. 1H-NMR analysis found that the levels of lactate, glucose, many kinds of amino acids, and fat acid decreased in serum. Elevated creatinine, trimetlylamine oxide (TMAO), acetate, lactate, glucose, many kinds of amino acids and decreased citrate, hippurate, and 2-oxoglutarate were found in urine. The predominant changes identified in kidney tissue involved the reduced levels of lactate and choline/phosphatidylcholine. Additionally, the alteration was noted between the proportion of the saturated and unsaturated fatty acid and phospholipid composition. Conclusion The data generated from the current study supports the fact that 1H-NMR technology is more sensitive than traditional urine and serum analysis. Glucose, amino acids, TMAO, and creatinine in urine could be identified as biomarkers of emodin induced renal injury.
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