TY - JOUR
T1 - Novel bioactivation pathway of benzbromarone mediated by cytochrome P450
AU - Kitagawara, Yumina
AU - Ohe, Tomoyuki
AU - Tachibana, Kumiko
AU - Takahashi, Kyoko
AU - Nakamura, Shigeo
AU - Mashino, Tadahiko
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
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.
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U2 - 10.1124/dmd.115.065037
DO - 10.1124/dmd.115.065037
M3 - Article
C2 - 26106235
AN - SCOPUS:84940385524
SN - 0090-9556
VL - 43
SP - 1303
EP - 1306
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 9
ER -