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.
Footnotes
- Received April 24, 2015.
- Accepted June 23, 2015.
This work was supported by Keio Gijuku Academic Development Funds; a grant from the Science Research Promotion Fund of the Japan Private School Promotion Foundation; and Platform for Drug Discovery, Informatics; and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT).
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- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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