YAKUGAKU ZASSHI
Online ISSN : 1347-5231
Print ISSN : 0031-6903
ISSN-L : 0031-6903
誌上シンポジウム
肝毒性を示す医薬品の代謝活性化機構の解析とそれに基づいた創薬戦略
大江 知之高橋 恭子中村 成夫増野 匡彦
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キーワード: hepatotoxicity, CYP, benzbromarone
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2017 年 137 巻 3 号 p. 249-255

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 Adverse reactions are one of the most important issues in drug development, as well as in the therapeutic usage of drugs during the post-approval stage. Specifically, idiosyncratic adverse drug reactions (IDR) occur in only a small group of patients who are treated with certain drugs, and are unpredictable. It is widely accepted that drug-induced IDR is often associated with CYP-mediated bioactivation. Benzbromarone (BBR) is effective in the treatment of hyperuricemia, and has been used as an effective drug in Japan for a long time. However, BBR has been associated with hepatotoxicity, including fatal liver injury. We identified 2,6-dibromohydroquinone (DBH) and mono-debrominated catechol (CAT) as novel metabolites of BBR in human and rat liver microsomal systems, by comparison with chemically synthesized authentic compounds via ipso-substitution, which we previously discovered to be a unique metabolic reaction of substituted phenols by CYP. Furthermore, CAT, DBH and the oxidized form of DBH (DBBQ) were highly cytotoxic in human hepatocellular carcinoma cells, compared with BBR. We consider that the formation of these metabolites from BBR is linked to the mechanism involved in BBR-induced hepatotoxicity because catechols, hydroquinones, and their oxidized forms are known to be toxic.

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© 2017 The Pharmaceutical Society of Japan
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