title: Inactivation of CYP3A4 by Benzbromarone in Human Liver Microsomes.
abstract: BACKGROUND
  Benzbromarone is a uricosuric drug in current clinical use that can cause serious hepatotoxicity. Chemically reactive and/or cytotoxic metabolites of benzbromarone have been identified; however there is a lack of available information on their role in benzbromarone hepatotoxicity. The reactive metabolites of some hepatotoxic drugs are known to covalently bind, or alternatively are targeted, to specific cytochrome P450 (P450) enzymes, a process that is often described as mechanism-based inhibition.
  
  
  OBJECTIVE
  We examined whether benzbromarone causes a mechanism-based inhibition of human P450 enzymes.
  
  
  METHODS
  Microsomes from human livers were preincubated with benzbromarone and NADPH, followed by evaluation of CYP2C9 and CYP3A4 activities.
  
  
  RESULTS
  Benzbromarone metabolism resulted in inhibition of CYP3A4 but not CYP2C9 in a time-dependent manner. Confirmation of pseudo-first order kinetics of inhibition, a requirement for NADPH, and a lack of protection by scavengers suggested that benzbromarone is a mechanism-based CYP3A4 inhibitor.
  
  
  CONCLUSIONS
  Modification of the P450 enzyme by the reactive metabolite is a common trait of drugs that induce idiosyncratic hepatotoxicity, and might provide a speculative, mechanistic model for the rare occurrences of this type of drug toxicity.
authors.affiliation: Laboratory of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, 15-8 Shiomi-cho, Choshi, Chiba 288-0025, Japan. ymasubuchi@cis.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Masubuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kondo
mesh_terms: D001553:Benzbromarone / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D008954:Models, Biological; D014528:Uricosuric Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D014528:Uricosuric Agents; D001553:Benzbromarone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human