Study on the Intervention Effect of DJ-1-binding Compound on Erlotinib-induced Hepatotoxicity

OBJECTIVE To investigate the hepatotoxicity induced by erlotinib, which was a small molecular tyrosine kinase inhibitor, and to observe the protective effect of DJ-1-binding compound Compound-23 on liver. METHODS To study the cytotoxic effect of erlotinib on cells in vitro, the effect on oxidative stress, and the changes of DJ-1 redox status in cultured Chang liver cell line. SD rats were randomly divided into 4 groups, including control group, erlotinib-induced liver injury model group, high dose and low dose of Compound-23 groups. The hepatotoxicity of erlotinib was studied in vivo, and the intervention effect of DJ-1-binding compound Compound-23 on erlotinib-induced hepatotoxicity was evaluated by detecting body weight of rats, the level of liver function index such as AST, ALT, LDH, the level of GSH, SOD, MDA in liver, liver necrosis, and apoptosis in rats. RESULTS Erlotinib caused hepatotoxicity both in vitro and in vivo, and induced the increase in ROS level, the decrease in isoelectric point of DJ-1, and the dissociation of DJ-1 dimer in cells, which indicated the oxidative stress status. High dose of DJ-1-binding compound Compound-23 group could significantly improve erlotinib-induced cell apoptosis damage, proliferation inhibition, weight loss, increase levels of liver function index and oxidative stress(P<0.05 or P<0.01), as well as necrosis and apoptosis degree in rats. CONCLUSION Erlotinib induce hepatotoxicity by induce oxidative stress and inhibit reduced activity of DJ-1 protein, DJ-1-binding compound Compound-23 protect the liver by reducing cell damage, improving liver function, and attenuating oxidative stress.