Acetaminophen (APAP) overdose is a leading cause of acute liver injury and is associated with high mortality. G protein-coupled receptor kinase 2 (GRK2) is a widely expressed serine/threonine kinase involved in the regulation of multiple cellular signaling pathways. Dysregulation of GRK2 expression has been linked to numerous pathological states, highlighting its potential contribution to disease mechanisms. However, its involvement in drug-induced acute liver injury is yet to be elucidated. This study explored the hepatoprotective effects of paroxetine, a GRK2 inhibitor, in the context of APAP-induced liver injury. Male C57BL/6 mice received an intraperitoneal injection of APAP (300 mg/kg), followed by oral administration of paroxetine (10 mg/kg) 30 min afterward. Paroxetine markedly decreased serum alanine aminotransferase and aspartate aminotransferase concentrations and reduced APAP-induced hepatocellular apoptosis and inflammation. Paroxetine also diminished hepatic neutrophil accumulation and decreased the expression of pro-inflammatory cytokines and chemokines. Furthermore, GRK2 inhibition alleviated oxidative stress, as evidenced by lower hepatic malondialdehyde concentrations and a partially restored glutathione (GSH)/GSH disulfide ratio. Importantly, inhibition of GRK2 resulted in a decrease in hepatic phosphorylation of extracellular signal-regulated kinase (ERK). Collectively, these results indicate that pharmacological inhibition of GRK2 by paroxetine confers protection against APAP-induced hepatotoxicity through anti-inflammatory and antioxidant actions, potentially mediated by modulation of ERK signaling.
Yang et al. (Mon,) studied this question.