论文部分内容阅读
Benzbromarone (BBR) is a benzofuran derivative that has been a quite useful drug for the treatment of gout.BBR has been being widely used in Asian countries.However, it was withdrawn from European markets in 2003, due to reported serious incidents of drug-induced liver injury.BBR-induced hepatotoxicity has been suggested to be associated with the formation of a quinone intermediate.The present study provided new insight into the mechanism of BBR-induced liver toxicity that involves bioactivation of BBR through epoxidation of the benzofuran ring to epoxide(s).In the present study, 24 h acute liver toxicity of BBR was evaluated in mice.Single intraperitoneal dose of BBR at 65 mg/kg was found to cause elevation of AST activity in serum.P450 enzyme induction with dexamethasone exacerbated BBR-induced hepatotoxicity.An N-acetyl cysteine (NAC) conjugate derived from epoxide metabolite(s) was detected in both microsomal incubations of BBR and urine samples of mice treated with BBR.The NAC conjugate was identified as 6-NAC BBR.Ketoconazole suppressed the bioactivation of BBR to the epoxide intermediate(s), and CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s).The results implicate a possible correlation between the formation of the epoxide metabolite(s) and hepatotoxicity of BBR.