Formation of a Quinoneimine Intermediate of 4-Fluoro-N-methylaniline by FMO1: Carbon Oxidation Plus Defluorination

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• 作者：James P. Driscoll ; Ignacio Aliagas ; Jennifer J. Harris ; Jason S. Halladay ; Sheerin Khatib-Shahidi ; Alan Deese ; Nathaniel Segraves ; S. Cyrus Khojasteh-Bakht
• 刊名：Chemical Research in Toxicology
• 出版年：2010
• 出版时间：May 17, 2010
• 年：2010
• 卷：23
• 期：5
• 页码：861-863
• 全文大小：127K
• 年卷期：v.23,no.5(May 17, 2010)
• ISSN：1520-5010

文摘

Here, we report on the mechanism by which flavin-containing monooxygenase 1 (FMO1) mediates the formation of a reactive intermediate of 4-fluoro-N-methylaniline. FMO1 catalyzed a carbon oxidation reaction coupled with defluorination that led to the formation of 4-N-methylaminophenol, which was a reaction first reported by Boersma et al. (Boersma et al. (1993) Drug Metab. Dispos.21, 218−230). We propose that a labile 1-fluoro-4-(methylimino)cyclohexa-2,5-dienol intermediate was formed leading to an electrophilic quinoneimine intermediate. The identification of N-acetylcysteine adducts by LC-MS/MS and NMR further supports the formation of a quinoneimine intermediate. Incubations containing stable labeled oxygen (H₂¹⁸O or ¹⁸O₂) and ab initio calculations were performed to support the proposed reaction mechanism.