title: Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan (Y.K., T.O., K.T., T.M.); Department of Chemistry, Nippon Medical School, Tokyo, Japan (S.N.).
authors.forename: Yumina
authors.initials: Y
authors.lastname: Kitagawara
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan (Y.K., T.O., K.T., T.M.); Department of Chemistry, Nippon Medical School, Tokyo, Japan (S.N.) ohe-tm@pha.keio.ac.jp mashino-td@pha.keio.ac.jp.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan (Y.K., T.O., K.T., T.M.); Department of Chemistry, Nippon Medical School, Tokyo, Japan (S.N.).
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tachibana
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan (Y.K., T.O., K.T., T.M.); Department of Chemistry, Nippon Medical School, Tokyo, Japan (S.N.).
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan (Y.K., T.O., K.T., T.M.); Department of Chemistry, Nippon Medical School, Tokyo, Japan (S.N.).
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Faculty of Pharmacy, Keio University, Tokyo, Japan (Y.K., T.O., K.T., T.M.); Department of Chemistry, Nippon Medical School, Tokyo, Japan (S.N.) ohe-tm@pha.keio.ac.jp mashino-td@pha.keio.ac.jp.
authors.forename: Tadahiko
authors.initials: T
authors.lastname: Mashino
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D001553:Benzbromarone / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001553:Benzbromarone; D003577:Cytochrome P-450 Enzyme System