Wei Lai, Liao Peiqiu, Wu Huifeng, Li Xiaojing, Pei Fengkui, Li Weisheng, Wu Yijie
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China.
Toxicol Appl Pharmacol. 2009 Feb 1;234(3):314-25. doi: 10.1016/j.taap.2008.11.010. Epub 2008 Nov 25.
The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of (1)H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. (1)H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.
采用对尿液、血清和肝组织水提取物的¹H NMR光谱进行代谢组学分析，在21天的时间里研究了雄性Wistar大鼠经灌胃给予雄黄（1 g/kg体重）后的毒理学效应。还进行了肝脏和肾脏组织病理学检查以及血清临床化学分析。来自雄黄处理动物的¹H NMR光谱和模式识别分析表明，尿中三羧酸循环中间体的排泄增加、尿液和血清中酮体水平升高、肝葡萄糖和糖原水平降低，以及低血糖和高脂血症，提示能量代谢受到干扰。血清和肝组织水提取物中含胆碱代谢物和甜菜碱水平升高以及血清肌酸增加表明转甲基作用改变。尿中氧化三甲胺、苯乙酰甘氨酸和马尿酸水平降低表明雄黄对肠道微生物群环境有影响。肝脏谷氨酸水平升高、血清中蛋氨酸增加和丙氨酸水平降低以及高牛磺酸尿症支持了氨基酸代谢受损的迹象。在肝组织水提取物中观察到的谷胱甘肽增加可能是雄黄诱导氧化损伤的生物标志物。血清临床化学分析显示乳酸脱氢酶、天冬氨酸转氨酶和碱性磷酸酶水平升高以及血尿素氮和肌酐水平升高，表明肝脏和肾脏有轻微损伤。利用模式识别方法实现了雄黄诱导的时间依赖性生化变化。这项工作说明了基于NMR的代谢组学方法在研究中药诱导的生化效应方面的高度可靠性。
