Investigations of drug-induced liver injury by a peroxynitrite activatable two-photon fluorescence probe.

Abstract

Drug-induced liver injury (DILI) is a prevalent liver disease and the leading cause for acute liver failure (ALF) worldwide. Screening of DILI in patients is central to ensure drug safety and improve therapy efficiency. Mounting evidences revealed that peroxynitrite (ONOO-) is involved in the DILI process and can be a potential biomarker for DILI. Thus far, there are few two-photon fluorescence probes for ONOO- that can accomplish this challenging task in DILI liver tissues. Hereby, a peroxynitrite activatable two-photon fluorescence probe BN-PN for the imaging of ONOO- in mice liver was elaborately constructed. The probe specifically reacted with peroxynitrite to furnish 140-fold fluorescence increase in vitro, which elucidated a high sensitivity for ONOO-. Thus, subtle changes of ONOO- levels in live cells can be sensitively imaged with this probe by two-photon microscopy. The probe also denoted the overproduction of ONOO- in APAP-induced liver injury, and proved that administration with NAC can effectively alleviate DILI and reduce ONOO- production in mouse liver. Further, the probe demonstrated the rapid rise of ONOO- level in the liver of DILI mice administrated with alcohol. This work disclosed the rational construction of a two-photon fluorescence probe-based DILI screening method, which would help the estimation of drug safety and new drug development.