title: Cysteine-Based Protein Adduction by Epoxide-Derived Metabolite(s) of Benzbromarone.
abstract: Benzbromarone (BBR) is a therapeutically useful uricosuric agent but can also cause acute liver injury. The hepatotoxicity of BBR is suggested to be associated with its metabolic activation. Our recent metabolic study demonstrated that BBR was metabolized to epoxide intermediate(s) by cytochrome P450 3A, and the intermediate(s) was reactive to N-acetylcysteine. The objectives of the present study were to determine the chemical identity of the interaction of protein with the epoxide intermediate(s) of BBR and to define the association of the protein modification with hepatotoxicity induced by BBR. Microsomal incubation study showed that the reactive intermediate(s) covalently modified microsomal protein at cysteine residues. Such adduction was also observed in hepatic protein obtained from liver of mice given BBR. The protein covalent binding occurred in time- and dose-dependent manners. Pretreatment with ketoconazole attenuated BBR-induced protein modification and hepatotoxicity, while pretreatment with dexamethasone or buthionine sulfoximine potentiated the protein adduction and hepatotoxicity induced by BBR. A good correlation was observed between BBR-induced hepatotoxicity and the epoxide-derived hepatic protein modification in mice. The present study provided in-depth mechanistic insight into BBR-induced hepatotoxicity.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yukun
authors.initials: Y
authors.lastname: Feng
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Xiucai
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University , Guiyang, Guizhou 550004, P. R. China.
authors.forename: Jiang
authors.identifier: 0000-0002-0340-0275
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001553:Benzbromarone / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry*; D004852:Epoxy Compounds / Q000737:chemistry*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011506:Proteins / Q000737:chemistry*; D066007:Toxicokinetics
chemical_list: D004852:Epoxy Compounds; D011506:Proteins; D001553:Benzbromarone; D005978:Glutathione; D003545:Cysteine