Mass spectrometry imaging reveals lipid upregulation and bile acid changes indicating amitriptyline induced steatosis in a rat model. (1st June 2020)

• Record Type: Journal Article
• Authors: Kampa, Judith M.; Sahin, Mikail; Slopianka, Markus; Giampà, Marco; Bednarz, Hanna; Ernst, Rainer; Riefke, Bjoern; Niehaus, Karsten; Fatangare, Amol
• Is Part Of: Toxicology letters. Volume 325(2020)
• Page Start: 43
• Page End: 50
• Publication Date: 2020-06-01
• Subjects: Drug induced steatosis (DIS) -- Drug induced liver injury (DILI) -- Macrovesicular steatosis -- MALDI -- Mass spectrometry imaging (MSI) -- Rat -- Toxicity -- Bile acids -- Phospholipids; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2020.02.007
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Amitriptyline induced alterations can be demonstrated via MALDI-MSI in rat liver. Amitriptyline and its metabolites accumulate throughout the liver tissue. Phosphatidylcholine (PC) species are increased in abundance upon Amitriptyline treatment. Histological findings and Oil Red O staining revealed macrovesicular steatosis. Two detected bile acids are decreased in Amitriptyline treatment group compared to control. Abstract: 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).