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Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450.
Kitagawara, Yumina; Ohe, Tomoyuki; Tachibana, Kumiko; Takahashi, Kyoko; Nakamura, Shigeo; Mashino, Tadahiko.
Affiliation
  • Kitagawara Y; 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 T; 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.
  • Tachibana K; 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.).
  • Takahashi K; 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.).
  • Nakamura S; 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.).
  • Mashino T; 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.
Drug Metab Dispos ; 43(9): 1303-6, 2015 Sep.
Article in En | MEDLINE | ID: mdl-26106235
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.
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Full text: 1 Database: MEDLINE Main subject: Benzbromarone / Cytochrome P-450 Enzyme System Limits: Animals / Humans Language: En Year: 2015 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Benzbromarone / Cytochrome P-450 Enzyme System Limits: Animals / Humans Language: En Year: 2015 Type: Article