PT  - JOURNAL ARTICLE
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
TI  - Metabolic Epoxidation Is a Critical Step for the Development of Benzbromarone-Induced Hepatotoxicity
AID  - 10.1124/dmd.117.077818
DP  - 2017 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 1354--1363
VI  - 45
IP  - 12
4099  - http://dmd.aspetjournals.org/content/45/12/1354.short
4100  - http://dmd.aspetjournals.org/content/45/12/1354.full
SO  - Drug Metab Dispos2017 Dec 01; 45
AB  - 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.