利用代谢组学技术研究中药关木通的肾毒性作用

本文利用代谢组学技术方法研究了染中药关木通毒性大鼠尿液的代谢改变及其与靶器官毒性的相关性。分3个剂量组(36、32、28g生药.kg-1.d-1)对雄性Wistar大鼠连续6d灌胃给药,收集12h的尿样,进行1H-NMR谱测定。实验结果表明,染毒后的大鼠尿样中氧化三甲胺、牛磺酸迅速下降,而柠檬酸、肌酐、2-酮戊二酸等代谢物也均有不同程度的下降;乙酸、丙氨酸则显著上升。主成分分析结果表明,给药组与对照组的代谢谱有明显差异,而造成组间差异的主要影响因素是乙酸、氧化三甲胺、丙氨酸和牛黄酸的变化。乙酸、丙氨酸的显著上升表明动物出现了肾小管坏死,与以前报道的肾脏病理和血浆生化改变相一致。关木通对动物的毒性作用有着明显的剂量依赖性。上述实验结果表明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,说明代谢组学方法在中药的毒性研究中有着潜在的应用前景。

Studying Nephrotoxicity of Aristolochia manshuriensis Using Metabonomics

NMR based metabonomic techniques have been used to study the changing metabolic profiles of urine samples collected from the male Wistar rats that are dosed with decoction of Aristolochia manshuriensis. The techniques are also used to study the relationship between the profiles and the target toxicity. Three groups of male Wistar rats were dosed by gavage with 36, 32 and 28g·kg-1·d-1 of Aristolochia manshuriensis, or the equal dosage of distilled water for 6 days,respectively. Urine samples were collected, and their 1H-NMR spectra obtained,before taken to data process and principal component analysis(PCA). Dramatic increase in acetate, and a lower degree of increase in alanine and lactate, was observed in all three dosed groups, though with more increase in the higher dose group. Urinary concentrations of TMAO, taurine and creatinine decreased sharply, with a gradual decrease in citrate and DMA in the dosed groups. The dosed groups can be readily discriminated from the controls ,based on principal component analysis(PCA), with acetate and TMAO as main discriminators.The increase of acetate and alanine in dosed groups suggested the renal tubular necrosis, in agreement with previous clinical chemistry and histopathological examination data. Results showed that Aristolochia manshutiensis can induce renal lesion in rats, as revealed by the metabonomic analysis of rat urine samples, and by blood biochemical analysis and histopathological examinations. Metabonomic approach is a promising new technique for studying the toxicology of Chinese medicine.