Xu J D, Xing W M, Yuan T J, Chen J, Lu H
School of Pharmacology, Zhejiang Chinese Medical University, Hangzhou, China.
School of Pharmacology, Zhejiang Chinese Medical University, Hangzhou, China
Hum Exp Toxicol. 2016 Feb;35(2):162-9. doi: 10.1177/0960327115579429. Epub 2015 Apr 7.
In recent years, andrographolide sodium bisulfite (ASB) has been reported to cause acute renal failure frequently in clinical practice. We hypothesized that changes in metabolic profile could have occurred after administration of ASB. To investigate the metabolic changes caused by ASB-induced nephrotoxicity, metabonomics method was utilized to depict the urine metabolic characteristics and find the specific urine biomarkers associated with ASB-induced nephrotoxicity. Sprague-Dawley rats were randomly assigned into three experimental groups. They received a single daily injection of vehicle (0.9% sodium chloride solution) or ASB at a dose of 100 or 600 mg kg(-1) day(-1) for 7 days. Twelve-hour urine was collected after the last administration. The routine urinalysis was measured by a urine automatic analyzer while urinary metabolites were evaluated using gas chromatography/mass spectrometry. The acquired data were processed by multivariate principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal PLS-DA. After 7-day administration of ASB, the positive urine samples in protein, occult blood, and ketones were increased, presenting dose dependence. The PCA and PLS-DA models were capable of distinguishing the difference between ASB-treated group and control. Biomarkers such as 1,5-anhydroglucitol, d-erythro-sphingosine, and 2-ketoadipate were identified as the most influential factors in ASB-induced nephrotoxicity.
近年来，临床实践中经常报道亚硫酸氢盐穿心莲内酯（ASB）可导致急性肾衰竭。我们推测，ASB给药后可能发生了代谢谱变化。为了研究ASB诱导的肾毒性所引起的代谢变化，采用代谢组学方法描绘尿液代谢特征，并寻找与ASB诱导的肾毒性相关的特定尿液生物标志物。将Sprague-Dawley大鼠随机分为三个实验组。它们每天接受一次载体（0.9%氯化钠溶液）或ASB注射，剂量分别为100或600 mg kg⁻¹天⁻¹，共7天。最后一次给药后收集12小时尿液。用尿液自动分析仪进行常规尿液分析，同时使用气相色谱/质谱法评估尿液代谢产物。对获取的数据进行多元主成分分析（PCA）、偏最小二乘判别分析（PLS-DA）和正交PLS-DA处理。ASB给药7天后，尿液中蛋白质、潜血和酮体的阳性样本增加，呈现剂量依赖性。PCA和PLS-DA模型能够区分ASB治疗组和对照组之间的差异。1,5-脱水葡萄糖醇、d-赤藓糖神经鞘氨醇和2-酮己二酸等生物标志物被确定为ASB诱导肾毒性的最有影响因素。
