5 years ago

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

Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes
Lin Yuan, Dan Cheng, Wang Xu, Xiaobing Zhang
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.

Publisher URL: http://dx.doi.org/10.1021/acs.analchem.7b01671

DOI: 10.1021/acs.analchem.7b01671

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