Novel Bioactivation Pathway of Benzbromarone Mediated by Cytochrome P450

被引：19

作者：

Kitagawara, Yumina ^{[1
]}

Ohe, Tomoyuki ^{[1
]}

Tachibana, Kumiko

Takahashi, Kyoko

Nakamura, Shigeo ^{[2
]}

Mashino, Tadahiko ^{[1
]}

机构：

[1] Keio Univ, Fac Pharm, Tokyo 1058512, Japan

[2] Nippon Med Sch, Dept Chem, Tokyo 113, Japan

来源：

DRUG METABOLISM AND DISPOSITION | 2015年 / 43卷 / 09期

关键词：

IPSO-SUBSTITUTION; OXYGEN-ATOM; METABOLIC PATHWAY; ELIMINATION; PHENOLS; INJURY; GOUT;

D O I：

10.1124/dmd.115.065037

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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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收藏

页码：1303 / 1306

页数：4

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