Abstract
Drug-induced liver injury (DILI) is an important cause of potentially fatal liver disease. Herein, we report the development of a molecular probe (LW-OTf) for the detection and imaging of two biomarkers involved in DILI. Initially, primary reactive oxygen species (ROS) superoxide (O2˙−) selectively activates a near-infrared fluorescence (NIRF) output by generating fluorophore LW-OH. The C Created by potrace 1.16, written by Peter Selinger 2001-2019 ]]> C linker of this hemicyanine fluorophore is subsequently oxidized by reactive nitrogen species (RNS) peroxynitrite (ONOO−), resulting in cleavage to release xanthene derivative LW-XTD, detected using two-photon excitation fluorescence (TPEF). An alternative fluorescence pathway can occur through cleavage of LW-OTf by ONOO− to non-fluorescent LW-XTD-OTf, which can react further with the second analyte O2˙− to produce the same LW-XTD fluorescent species. By combining NIRF and TPEF, LW-OTf is capable of differential and simultaneous detection of ROS and RNS in DILI using two optically orthogonal channels. Probe LW-OTf could be used to detect O2˙− or O2˙− and ONOO− in lysosomes stimulated by 2-methoxyestradiol (2-ME) or 2-ME and SIN-1 respectively. In addition, we were able to monitor the chemoprotective effects of tert-butylhydroxyanisole (BHA) against acetaminophen (APAP) toxicity in living HL-7702 cells. More importantly, TPEF and NIRF imaging confirmed an increase in levels of both O2˙− and ONOO− in mouse livers during APAP-induced DILI (confirmed by hematoxylin and eosin (H&E) staining).
Highlights
Drug-induced liver injury (DILI) is a leading cause of acute liver failure in the USA and Europe, and has as such raised serious concerns for public health.[1,2,3] The potential to induce DILI is one of the most common causes of compound attrition in drug development, o en leading to drug withdrawals, restrictions, and project termination.[3]
These observations are in good agreement with the proposed mechanism for the sequential reaction of LW-OTf with O2cÀ followed by ONOOÀ (Scheme 1)
Since overdose of APAP leads to the overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS),[54] APAP-induced DILI was chosen as a representative model for liver toxicity in which to evaluate the effectiveness of LW-OTf
Summary
Drug-induced liver injury (DILI) is a leading cause of acute liver failure in the USA and Europe, and has as such raised serious concerns for public health.[1,2,3] The potential to induce DILI is one of the most common causes of compound attrition in drug development, o en leading to drug withdrawals, restrictions, and project termination.[3]. Excitation at 360 nm was selected for onephoton uorescence experiments, matching the observed maximum absorption for LW-XTD at 353 nm, as well as previous reports of this system.[38] LW-OTf initially exhibited a weak emission signal at 461 nm in the presence of O2cÀ, upon subsequent addition of ONOOÀ the D–p–A-based oxidation product LW-XTD exhibited a strong uorescence emission at 461 nm, upon excitation at 360 nm (Fig. 2a).
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