Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes

Abstract

Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO and Rhod-ONOO) for ONOO through a novel and universally applicable mechanism: ONOO-mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO can selectively accumulate and react in mitochondria, one of the main sources of ONOO, with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.

The role of reactive oxygen species in tumor treatment

“…35,36 Fluorescence analysis is widely used because uorescence probe has good stability, cell membrane permeability and low cytotoxicity. 37,38 The working principle of EPR is that the microwave energy resonates with atoms, ions or molecules of unpaired electrons under the action of a stable magnetic eld. 33 However, the direct detection of ROS in actual samples using EPR spectroscopy is oen difficult owing to the instability of ROS.…”

Visualization of oxidative injury in the mouse kidney using selective superoxide anion fluorescent probes

“…The hydroxyl naphthalimide chromophore was selected as a signal platform due to its high fluorescence quantum yield, outstanding photostability and excellent two-photon properties. 44 Accordingly, some potential protective groups were introduced into the hydroxyl group of chromophores as the reaction site of O 2 ˙ – , including trifluoromethanesulfonate, 2,4-dinitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, and diphenyl phosphinated, to afford compounds 1–4 ( Scheme 1B ).…”

The Conquering influence of the Nano extracts of pomegranate peels and pistachio leaves in amelioration of acute liver failure

“…The TAA biotransformation cycle into thioacetamide sulfoxide (TAAS) mainly takes place through P450 (CYP) cytochrome pathway, (CYP2E enzyme is mainly involved here) [12] . The binding of these metabolites to liver macromolecules dramatically inspire a moiety of reactive oxygen species in turn induces acute centrilobular necrosis of the liver [13] . These results of the liver diseases such as cirrhosis and primary cancer of the liver [14].…”