کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5547177 | 1402783 | 2017 | 7 صفحه PDF | دانلود رایگان |
Benzbromarone (BBR) is a potent uricosuric drug that can cause serious liver injury. Our recent study suggested that 1â²-hydroxy BBR, one of major metabolites of BBR, is metabolized to a cytotoxic metabolite that could be detoxified by glutathione (GSH). The aim of this study was to clarify whether GSH adducts are formed from 1â²-hydroxy BBR in human liver microsomes (HLM). Incubation of 1â²-hydroxy BBR with GSH in HLM did not result in the formation of GSH adducts, but 1â²,6-dihydroxy BBR was formed. In addition, incubation of 1â²,6-dihydroxy BBR with GSH in HLM resulted in the formation of three novel GSH adducts (M1, M2 and M3). The structures of M1 and M2 were estimated to be GSH adducts in which the 1-hydroxyethyl group at the C-2 position and the hydroxyl group at the C-1â² position of 1â²,6-dihydroxy BBR were substituted by GSH, respectively. We also found that the 6-hydroxylation of 1â²-hydroxy BBR is mainly catalyzed by CYP2C9 and that several CYPs and/or non-enzymatic reaction are involved in the formation of GSH adducts from 1â²,6-dihydroxy BBR. The results indicate that 1â²-hydroxy BBR is metabolized to reactive metabolites via 1â²,6-dihydroxy BBR formation, suggesting that these reactive metabolites are responsible for BBR-induced liver injury.
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Journal: Drug Metabolism and Pharmacokinetics - Volume 32, Issue 1, February 2017, Pages 46-52