title: Identification of Epoxide-Derived Metabolite(s) of Benzbromarone.
abstract: Benzbromarone (BBR) is a benzofuran derivative that has been quite useful for the treatment of gout; however, it was withdrawn from European markets in 2003 because of reported serious incidents of drug-induced liver injury.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 reported epoxide-derived intermediate(s) of BBR. An N-acetylcysteine (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 the CYP3A subfamily was the primary enzyme responsible for the formation of the epoxide(s). The present study provided new information on metabolic activation of BBR.
authors.affiliation: School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.).
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.).
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.) zhengneu@yahoo.com yingpeng1999@163.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: School of Pharmacy (K.W., H.W., Y.P.), Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education (J.Z.), Shenyang Pharmaceutical University, Shenyang, Liaoning, P. R. China; and Center for Developmental Therapeutics, Seattle Children's Research Institute, Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington (J.Z.).
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001553:Benzbromarone / Q000737:chemistry / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D014528:Uricosuric Agents / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004852:Epoxy Compounds; D014528:Uricosuric Agents; D001553:Benzbromarone