Pharmacological inhibition of G protein–coupled receptor kinase 2 (GRK2) by paroxetine attenuates acetaminophen-induced hepatotoxicity

초록

Acetaminophen (APAP) overdose is a leading cause of acute liver injuryand is associated with high mortality. G protein–coupled receptor kinase 2 (GRK2)is a widely expressed serine/threonine kinase involved in the regulation of multiplecellular signaling pathways. Dysregulation of GRK2 expression has been linked tonumerous pathological states, highlighting its potential contribution to diseasemechanisms. However, its involvement in drug-induced acute liver injury is yet to beelucidated. This study explored the hepatoprotective effects of paroxetine, a GRK2inhibitor, in the context of APAP-induced liver injury. Male C57BL/6 mice received anintraperitoneal injection of APAP (300 mg/kg), followed by oral administration of paroxetine(10 mg/kg) 30 min afterward. Paroxetine markedly decreased serum alanineaminotransferase and aspartate aminotransferase concentrations and reduced APAPinducedhepatocellular apoptosis and inflammation. Paroxetine also diminishedhepatic neutrophil accumulation and decreased the expression of pro-inflammatorycytokines and chemokines. Furthermore, GRK2 inhibition alleviated oxidative stress,as evidenced by lower hepatic malondialdehyde concentrations and a partially restoredglutathione (GSH)/GSH disulfide ratio. Importantly, inhibition of GRK2 resultedin a decrease in hepatic phosphorylation of extracellular signal-regulated kinase(ERK). Collectively, these results indicate that pharmacological inhibition of GRK2 byparoxetine confers protection against APAP-induced hepatotoxicity through antiinflammatoryand antioxidant actions, potentially mediated by modulation of ERKsignaling.

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