Abstract
Benzbromarone (BBR) is effective in the treatment of gout but can also cause fatal hepatic failure in clinic. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) which 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 (6-F-, Cl-, or Br-BBR) to decrease the potential for P450-mediated metabolic activation. Both in vitro and in vivo uricosuric activity assays showed that the fluorinated BBR (6-F-BBR) achieved favorable uricosuric effect, while the chlorinated BBR (6-Cl-BBR) and brominated BBR (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 GSH 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 for the development of BBR-induced hepatotoxicity.
- The American Society for Pharmacology and Experimental Therapeutics