关木通肾毒性的代谢组学研究

Metabonomics study on nephrotoxicity of Aristolochia manshuriensis

目的研究经关木通染毒后大鼠尿液的代谢表型改变及其与组织病理和尿液、血浆生化指标的相关性,探讨代谢组学在中药毒理学研究中的应用。方法关木通分4个剂量组:36、32、28、24 g/kg,W istar大鼠连续ig给药6 d,12 h后收集尿样,测定1H-NM R谱,并进行血浆生化指标和肾脏组织病理学检查。结果染毒后,大鼠肾脏出现不同程度的炎症坏死,尿样中氧化三甲胺、柠檬酸、牛磺酸、肌酐、甜菜碱等代谢物均有不同程度的下降,而醋酸、丙氨酸则显著上升。主成分分析表明,给药组与对照组的代谢谱有明显差异,能够被区分开,而造成组间差异的主要影响因素是醋酸和氧化三甲胺的变化。不同剂量条件下,各组动物的代谢谱也各不相同,与肾脏病理和血浆生化改变相一致。结论关木通能够对肾脏造成损害,且大鼠尿液的代谢物谱与关木通毒性作用强度密切相关,代谢组学分析方法在毒理学研究中有着广泛的应用前景。

Objective To study the metabolic profiles in the urine samples of rats dosed with decoction of the caulis of Aristolochia manshuriensis and the relationship between the results of blood biochemical analysis and histopathological analysis, and to explore the feasibility of the application of NMR-based metabonomics to toxicology of Chinese medicine. Methods Male Wistar rats were administrated by ig 36, 32, 28, and 24 g/kg of A. manshuriensis or the equal volume of distilled water for 6 d, respectively. Urine were collected and their ^1H-NMR spectra were acquired, and then subjected to data process and principal component ana-lysis （PCA）. Blood biochemical analysis and histopathological examination were carried out. Results Compared to control groups, the urinary concentrations of TMAO, taurine, creatinine, DMG, citrate; and DMA in dosed groups decreased, while those of acetate, alanine, and some other amino acids increased to a great extent. The dosed groups can be readily discriminated from the controls based on PCA, with acetate and TMAO as main discriminators. A good agreement was achieved within clinical chemistry, microscopically examination and PCA data. Conclusion The caulis of A. manshuriensis can induce renal lesion as revealed by the metabonomic analysis of rat urine samples as well as blood biochemical analysis and histopathological examinations. The results show that the metabonomic approach is a promising new technology in toxicology.