Tan Yong, Ko Joshua, Liu Xinru, Lu Cheng, Li Jian, Xiao Cheng, Li Li, Niu Xuyan, Jiang Miao, He Xiaojuan, Zhao Hongyan, Zhang Zhongxiao, Bian Zhaoxiang, Yang Zhijun, Zhang Ge, Zhang Weidong, Lu Aiping
Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Mol Biosyst. 2014 Jul 29;10(9):2305-16. doi: 10.1039/c4mb00072b.
We recently reported that processed Aconitum carmichaelii Debx (Bai-Fu-Pian in Chinese, BFP) elicits differential toxic responses in rats under various health conditions. The present study aimed to determine the graded toxicity of BFP so as to derive a safe therapeutic rationale in clinical practice. Sensitive and reliable biomarkers of toxicity were also identified, with the corresponding metabolic pathways being unveiled. Thirty male Sprague-Dawley rats were divided into five groups (n = 6) and received oral administration of BFP extract (0.32, 0.64, 1.28 or 2.56 g kg(-1) per day) or an equal volume of drinking water (control) for 15 days. The metabolomic profiles of rat serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry (LC-Q-TOF-MS). Linear regression analysis and Ingenuity Pathway Analysis (IPA) were used to elucidate the differentiated altered metabolites and associated network relationships. Results from biochemical and histopathological examinations revealed that BFP could induce prominent toxicity in the heart, liver and kidneys at a dose of 2.56 g kg(-1) per day. Betaine up-regulation and phosphatidylcholine down-regulation were detected in the serum samples of drug-treated groups in a dose-dependent manner. In summary, betaine and phosphatidylcholine could be regarded as sensitive biomarkers for the toxic responses of BFP. Perturbations of RhoA signaling, choline metabolism and free radical scavenging were found to be partly responsible for the toxic effects of the herbal drug. Based on the metabolomics findings, we could establish a safe therapeutic range in the clinical use of BFP, with promising predictions of possible drug toxicity.
我们最近报道，炮制后的乌头（中药名为白附片，BFP）在不同健康状况的大鼠中会引发不同的毒性反应。本研究旨在确定BFP的分级毒性，以便在临床实践中得出安全的治疗依据。还鉴定了敏感且可靠的毒性生物标志物，并揭示了相应的代谢途径。将30只雄性Sprague-Dawley大鼠分为五组（每组n = 6），分别口服BFP提取物（每天0.32、0.64、1.28或2.56 g kg⁻¹）或等体积的饮用水（对照组），持续15天。采用液相色谱四极杆飞行时间质谱（LC-Q-TOF-MS）分析大鼠血清的代谢组学谱。使用线性回归分析和 Ingenuity 通路分析（IPA）来阐明差异改变的代谢物及其相关的网络关系。生化和组织病理学检查结果显示，每天2.56 g kg⁻¹的BFP剂量可在心脏、肝脏和肾脏中诱导明显的毒性。在药物治疗组的血清样本中检测到甜菜碱上调和磷脂酰胆碱下调，且呈剂量依赖性。综上所述，甜菜碱和磷脂酰胆碱可被视为BFP毒性反应的敏感生物标志物。发现RhoA信号传导、胆碱代谢和自由基清除的扰动部分导致了该草药的毒性作用。基于代谢组学研究结果，我们可以确定BFP临床使用的安全治疗范围，并对可能的药物毒性做出有前景的预测。
