Proteome and Metabolome Research, Center for Biotechnology (CeBiTec), Faculty of Biology, Bielefeld University, Bielefeld, Germany.
Metabolic Profiling and Clinical Pathology, Investigational Toxicology, Pharmaceuticals Division, Bayer AG, Berlin, Germany.
Toxicol Lett. 2020 Jun 1;325:43-50. doi: 10.1016/j.toxlet.2020.02.007. Epub 2020 Feb 21.
As a consequence of the detoxification process, drugs and drug related metabolites can accumulate in the liver, resulting in drug induced liver injury (DILI), which is the major cause for dose limitation. Amitriptyline, a commonly used tricyclic anti-depressant, is known to cause DILI. The mechanism of Amitriptyline induced liver injury is not yet completely understood. However, as it undergoes extensive hepatic metabolism, unraveling the molecular changes in the liver upon Amitriptyline treatment can help understand Amitriptyline's mode of toxicity. In this study, Amitriptyline treated male rat liver tissue was analyzed using Matrix Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging (MALDI-MSI) to investigate the spatial abundances of Amitriptyline, lipids, and bile acids. The metabolism of Amitriptyline in liver tissue was successfully demonstrated, as the spatial distribution of Amitriptyline and its metabolites localize throughout treatment group liver samples. Several lipids appear upregulated, from which nine were identified as distinct phosphatidylcholine (PC) species. The detected bile acids were found to be lower in Amitriptyline treatment group. The combined results from histological findings, Oil Red O staining, and lipid zonation by MSI revealed lipid upregulation in the periportal area indicating drug induced macrovesicular steatosis (DIS).
由于解毒过程，药物和与药物相关的代谢物会在肝脏中积累，导致药物性肝损伤（DILI），这是限制剂量的主要原因。阿米替林是一种常用的三环抗抑郁药，已知会引起 DILI。阿米替林诱导肝损伤的机制尚未完全阐明。然而，由于它经历了广泛的肝脏代谢，因此研究阿米替林治疗后肝脏中的分子变化有助于了解阿米替林的毒性模式。在这项研究中，使用基质辅助激光解吸/电离 - 质谱成像（MALDI-MSI）分析了阿米替林治疗的雄性大鼠肝组织，以研究阿米替林、脂质和胆汁酸的空间丰度。成功证明了阿米替林在肝组织中的代谢，因为阿米替林及其代谢物的空间分布定位于整个治疗组肝样品中。几种脂质上调，其中九种被鉴定为不同的磷脂酰胆碱（PC）种类。在阿米替林治疗组中发现检测到的胆汁酸较低。组织学发现、油红 O 染色和 MSI 的脂质分区的综合结果显示，门脉周围区域的脂质上调表明药物诱导的大泡性脂肪变性（DIS）。
