Novel bioactivation pathway of benzbromarone mediated by cytochrome P450

Yumina Kitagawara, Tomoyuki Ohe, Kumiko Tachibana, Kyoko Takahashi, Shigeo Nakamura, Tadahiko Mashino

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1303-1306
Number of pages4
JournalDrug Metabolism and Disposition
Issue number9
Publication statusPublished - 2015 Sept 1

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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