Jiang Lei, Si Zhi-Hong, Li Ming-Hui, Zhao He, Fu Yong-Hong, Xing Yue-Xiao, Hong Wei, Ruan Ling-Yu, Li Pu-Min, Wang Jun-Song
Centre for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing 210094, PR China.
Centre for Molecular Metabolism, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei Street, Nanjing 210094, PR China.
J Pharm Biomed Anal. 2017 Mar 20;136:44-54. doi: 10.1016/j.jpba.2016.12.033. Epub 2016 Dec 29.
Ginkgolic acid (15:1) is a major toxic component in extracts obtained from Ginkgo biloba (EGb) that has allergic and genotoxic effects. This study is the first to explore the hepatotoxicity of ginkgolic acid (15:1) using a NMR (nuclear magnetic resonance)-based metabolomics approach in combination with biochemistry assays. Mice were orally administered two doses of ginkgolic acid (15:1), and mouse livers and serum were then collected for NMR recordings and biochemical assays. The levels of activity of alanine aminotransferase (ALT) and glutamic aspartate transaminase (AST) observed in the ginkgolic acid (15:1)-treated mice suggested that it had induced severe liver damage. An orthogonal signal correction partial least-squares discriminant analysis (OSC-PLSDA) performed to determine the metabolomic profile of mouse liver tissues indicated that many metabolic disturbances, especially oxidative stress and purine metabolism, were induced by ginkgolic acid (15:1). A correlation network analysis combined with information related to structural similarities further confirmed that purine metabolism was disturbed by ginkgolic acid (15:1). This mechanism might represent the link between the antitumour activity and the liver injury-inducing effect of ginkgolic acid (15:1). A SUS (Shared and Unique Structure) plot suggested that a two-dose treatment of ginkgolic acid (15:1) had generally the same effect on metabolic variations but that its effects were dose-dependent, revealing some of the common features of ginkgolic acid (15:1) dosing. This integrated metabolomics approach helped us to characterise ginkgolic acid (15:1)-induced liver damage in mice.
银杏酸（15:1）是从银杏叶提取物（EGb）中获得的主要毒性成分，具有过敏和基因毒性作用。本研究首次采用基于核磁共振（NMR）的代谢组学方法结合生化分析，探讨银杏酸（15:1）的肝毒性。给小鼠口服两剂银杏酸（15:1），然后收集小鼠肝脏和血清进行NMR记录和生化分析。在银杏酸（15:1）处理的小鼠中观察到的丙氨酸转氨酶（ALT）和谷氨酸天冬氨酸转氨酶（AST）活性水平表明，它已导致严重的肝损伤。为确定小鼠肝脏组织的代谢组学特征而进行的正交信号校正偏最小二乘判别分析（OSC-PLSDA）表明，银杏酸（15:1）诱导了许多代谢紊乱，尤其是氧化应激和嘌呤代谢。结合与结构相似性相关信息的相关网络分析进一步证实，嘌呤代谢受到银杏酸（15:1）的干扰。这种机制可能代表了银杏酸（15:1）的抗肿瘤活性和肝损伤诱导作用之间的联系。SUS（共享和独特结构）图表明，两剂银杏酸（15:1）处理对代谢变化通常具有相同的影响，但其影响具有剂量依赖性，揭示了银杏酸（15:1）给药的一些共同特征。这种综合代谢组学方法有助于我们描述银杏酸（15:1）诱导的小鼠肝损伤特征。
