TY - JOUR T1 - Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1303 LP - 1306 DO - 10.1124/dmd.115.065037 VL - 43 IS - 9 AU - Yumina Kitagawara AU - Tomoyuki Ohe AU - Kumiko Tachibana AU - Kyoko Takahashi AU - Shigeo Nakamura AU - Tadahiko Mashino Y1 - 2015/09/01 UR - http://dmd.aspetjournals.org/content/43/9/1303.abstract N2 - Benzbromarone (BBR) is a hepatotoxic drug, but the detailed mechanism of its toxicity remains unknown. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (2-ethyl-3-(3-bromo-4,5-dihydroxybenzoyl)benzofuran; CAT) as novel metabolites of BBR in rat and human liver microsomal systems by comparison with chemically synthesized authentic compounds, and we also elucidated that DBH is formed by cytochrome P450 2C9 and that CAT is formed mainly by CYP1A1, 2D6, 2E1, and 3A4. Furthermore, CAT, DBH, and the oxidized form of DBH are highly cytotoxic in HepG2 compared with BBR. Taken together, our data demonstrate that DBH, a novel reactive metabolite, may be relevant to BBR-induced hepatotoxicity. ER -