Investigation into Drug-Induced Liver Damage Using Multimodal Mass Spectrometry Imaging

• DOI: 10.1021/jasms.4c00313
• Publication Date: 2025-01-18T03:23:19Z
• Authors: Bryn Flinders; Lennart Huizing; Bhanu Singh; Heng-Keang Lim; Marjolein van Hee...; Filip Cuyckens; Ron M. A. Heeren; Rob J. Vreeken
• Keywords: Mass spectrometry imaging

Drug toxicity during the development of candidate pharmaceuticals is leading cause discontinuation in preclinical drug discovery and development. Traditionally, often determined by histological examination, clinical pathology, detection drugs and/or metabolites liquid chromatography–mass spectrometry (LC-MS). While these techniques individually provide information on pathological effects metabolites, they cannot specific molecular spatial without additional experiments. Matrix-assisted laser desorption/ionization-mass imaging (MALDI-MSI) a powerful, label-free technique for simultaneous pharmaceuticals, endogenous chemical species tissue sections, which makes it suitable mechanistic toxicological studies to directly correlate distribution its with findings. This capability was demonstrated analysis liver from dogs dosed discontinued compound B N-desmethyl metabolite, A. Histological examination showed multifocal hepatocellular necrosis, bile duct hyperplasia, periportal fibrosis, chronic inflammation. MALDI-MSI only A indicated that lesions were associated exclusively parent compound, whereas presence two (compound an N-oxide metabolite). Using both positive negative ion modes, identification markers connective tissue, blood vessels, parenchyma, epithelium achieved, allowing optimal visualization mass imaging.