RT Journal Article
SR Electronic
T1 Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1303
OP 1306
DO 10.1124/dmd.115.065037
VO 43
IS 9
A1 Yumina Kitagawara
A1 Tomoyuki Ohe
A1 Kumiko Tachibana
A1 Kyoko Takahashi
A1 Shigeo Nakamura
A1 Tadahiko Mashino
YR 2015
UL http://dmd.aspetjournals.org/content/43/9/1303.abstract
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.