TY - JOUR T1 - Metabolic Epoxidation Is a Critical Step for the Development of Benzbromarone-Induced Hepatotoxicity JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1354 LP - 1363 DO - 10.1124/dmd.117.077818 VL - 45 IS - 12 AU - Hui Wang AU - Ying Peng AU - Tingjian Zhang AU - Qunsheng Lan AU - Huimin Zhao AU - Wenbao Wang AU - Yufei Zhao AU - Xu Wang AU - Jianxin Pang AU - Shaojie Wang AU - Jiang Zheng Y1 - 2017/12/01 UR - http://dmd.aspetjournals.org/content/45/12/1354.abstract N2 - Benzbromarone (BBR) is effective in the treatment of gout; however, clinical findings have shown it can also cause fatal hepatic failure. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) that reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives, fluorinated BBR (6-F-BBR), chlorinated BBR (6-Cl-BBR), and brominated BBR (6-Br-BBR), to decrease the potential for cytochrome P450–mediated metabolic activation. Both in vitro and in vivo uricosuric activity assays showed that 6-F-BBR achieved favorable uricosuric effect, while 6-Cl-BBR and 6-Br-BBR showed weak uricosuric efficacy. Additionally, 6-F-BBR elicited much lower hepatotoxicity in mice. Fluorination of BBR offered advantage to metabolic stability in liver microsomes, almost completely blocked the formation of epoxide metabolite(s) and protein covalent binding, and attenuated hepatic and plasma glutathione depletion. Moreover, the structural manipulation did not alter the efficacy of BBR. This work provided solid evidence that the formation of the epoxide(s) is a key step in the development of BBR-induced hepatotoxicity. ER -