Screening drug-induced liver injury through two independent parameters of lipid droplets and peroxynitrite with a π-extended coumarin-based NIR fluorescent probe

Abstract

Drug-induced liver injury (DILI) or hepatotoxicity is a significant concern for public health. However, relying on a single biomarker for early DILI diagnosis poses a high risk of false positives. In this study, we reported a near-infrared fluorescent probe (BCOU-S), which enables independent visualization of LDs status and ONOO[sbnd] fluctuations. BCOU-S was constructed by combining a π-extended coumarin core as the NIR fluorophore and a methyl thioether group as the ONOO[sbnd] recognition site. BCOU-S could emit 655 nm NIR fluorescence excited at 518 nm, with a low detection limit of 27 nM and a large Stokes shift of 137 nm. The response mechanism to ONOO[sbnd] was confirmed by molecular orbital density function theory (DFT) and time-dependent DFT (TD-DFT) calculations. BCOU-S monitors LDs status through co-localization, oleic acid (OA) incubation, and starvation induction experiments. It sensitively distinguishes subtle changes in ONOO[sbnd] induced by different drugs in DILI cell models. In the acetaminophen (APAP)-induced DILI model, BCOU-S reveals significant LDs accumulation and increase in ONOO[sbnd] levels, establishing a clear time-effect and dose-effect relationship. Simultaneously monitoring ONOO[sbnd] levels and LDs accumulation, BCOU-S proves to be a more sensitive and effective tool for early DILI prevention, effectively avoiding false positives caused by changes in a single parameter. BCOU-S is a useful tool for further monitoring early DILI development. © 2024 Elsevier B.V.