NF-κB-targeted intervention of acetaminophen-induced acute liver injury by benzyl indanone

Abstract

Abstract Acetaminophen (APAP, Paracetamol) is a worldwide analgesic ingredient. Acetaminophen overdose accounts for 46% of acute liver failure. The toxic mechanism of acetaminophen-induced liver injury (AILI) consists of two phases: early phase by APAP and late phase by Kupffer cell-mediated inflammation. N-acetyl cysteine, the therapeutic drug of AILI, is effective in early phase but not in late phase. Here, we focus on the innate immunosuppressant to improve AILI and demonstrate protective effect of benzyl indanone derivative on AILI. The survival rate of AILI was increased from 12% to 91% and serum levels of ALT, AST and total bilirubin was decreased by benzyl indanone derivatives. It was associated with decreased hepatic necrosis, DNA fragmentation, neutrophil infiltration and expression levels of pro-inflammatory cytokines and chemokines. We isolated hepatocyte and kupffer cell to determine molecular target of benzyl indanone derivative. Benzyl indanone derivative did not affect primary hepatic damage such as ROS production, JNK phosphorylation, mitochondrial membrane potential and cell death. Benzyl indanone derivative reduced NO production and pro-inflammatory cytokine/chemokine expression in Kupffer cell. Benzyl indanone derivative reduced DNA binding affinity and transcriptional activity of NF-κB but did not affact NF-κB phosphorylation and nuclear import. This study suggest that inhibition of NF-κB activity by benzyl indanone derivative improves AILI.