The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity

Abstract

Acetaminophen (APAP)-induced hepatotoxicity comes among the most frequent humans’ toxicities caused by drugs. So far, therapeutic interventions for such type of drug-induced toxicity are still limited. In the current study, we examined the influence of capmatinib (Cap), a novel c-Met inhibitor, on APAP-induced hepatotoxicity in mice when administered 2 h prior, 2 h post and 4 h post APAP-challenge. The results revealed that Cap administration significantly attenuated APAP-induced liver injury when administered only 2 h prior and post APAP-administration. Cap hepatoprotective effect was mediated by lowering the excessive formation of lipid peroxidation and nitrosative stress products caused by APAP. Besides, Cap attenuated APAP-induced overproduction and release of proinflammatory mediators like TNF-α, IL-1β, IL-17A, IL-6, and MCP-1. Cap treatment also led to avoidance of APAP-subsequent repair by abating APAP-induced elevation of hepatic IL-22 and PCNA expressions. In conclusion, c-Met receptor inhibition may be a potential strategy for alleviating APAP-hepatotoxicity, especially when administered in the early phase of intoxication.