PT - JOURNAL ARTICLE AU - Yumina Kitagawara AU - Tomoyuki Ohe AU - Kumiko Tachibana AU - Kyoko Takahashi AU - Shigeo Nakamura AU - Tadahiko Mashino TI - Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450 AID - 10.1124/dmd.115.065037 DP - 2015 Sep 01 TA - Drug Metabolism and Disposition PG - 1303--1306 VI - 43 IP - 9 4099 - http://dmd.aspetjournals.org/content/43/9/1303.short 4100 - http://dmd.aspetjournals.org/content/43/9/1303.full SO - Drug Metab Dispos2015 Sep 01; 43 AB - 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.