Additional Pathways of S-Conjugate Formation during Interaction of 4-Nitrosophenetole with Glutathione

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• 作者：Dieter Gallemann ; Anke Greif ; Peter Eyer ; Hans-Ulrich Wagner ; Johann Sonnenbichler ; Isolde Sonnenbichler ; Wolfram Sch&auml ; fer ; and Ingrid Buhrow
• 刊名：Chemical Research in Toxicology
• 出版年：1998
• 出版时间：December 1998
• 年：1998
• 卷：11
• 期：12
• 页码：1411 - 1422
• 全文大小：170K
• 年卷期：v.11,no.12(December 1998)
• ISSN：1520-5010

文摘

The rapid reactions of nitrosoarenes with cellular SH groups have proved to be main metabolicconversions during detoxication. Interactions of the phenacetin metabolite 4-nitrosophenetolewith glutathione have been investigated in detail during the last years, revealing a complexpattern of products depending on the stoichiometry of the reactants and reaction conditions.Eight metabolites have been identified hitherto, and the present work extends this medley bysix additional products. Three metastable sulfenamides, 4-ethoxy-2,N-bis(glutathion-S-yl)-aniline, N⁴-(glutathion-S-yl)-4-amino-4'-ethoxydiphenylamine, and N-(glutathion-S-yl)-4-aminophenol, as well as the N-sulfenylquinonimine N-(glutathion-S-yl)-1,4-benzoquinonimine werecharacterized by chemical reactivity, chromatographic behavior, UV/vis absorption, ¹H NMR,and FAB-MS data. The structure of the sulfenamide 2,N⁴-bis(glutathion-S-yl)-4-amino-4'-ethoxydiphenylamine could not be proved unequivocally, but is strongly suggested due to thechemical reactivity, chromatographic behavior, and UV/vis absorption of the compound. Finally,traces of 4-aminophenol were detected. A reaction scheme is presented explaining the formationof all identified metabolites via a central sulfenamide cation. Molecular orbital calculationsfor this sulfenamide cation have been performed, corroborating the proposed reactionmechanisms on the basis of Klopman's generalized perturbation theory.