Additional pathways of S-conjugate formation during interaction of 4-nitrosophenetole with glutathione

The rapid reactions of nitrosoarenes with cellular SH groups have proved to be main metabolic conversions during detoxication. Inter actions of the ph enacetin metabolite 4-nitrosophenetole with glutathione have been investiga ted in detail during the last years, revealing a complete pattern of produc ts depending on the stoichiometry of the reactants and reaction conditions Eight metabolites have been identified hitherto, and the present work exten ds this medley by six additional products. Three metastable sulfenamides, 4 -ethoxy-2,N-bis(glutathion-S-yl)-aniline, N-4-glutathion-S-yl)-4-amino-4'-e thoxydiphenylamine, and N-(glutathion-S-yl)-4-aminophenol, as well as the N -sulfenylquinonimine N-(glutathion-S-yl)-1,4-benzoquinonimine were characte rized by chemical reactivity, chromatographic behavior, UV/vis absorption, H-1 NMR, and FAB-MS data. The structure of the sulfenamide 2,N-4-bis(glutat hion-S-yl)-4-amino-4'-ethoxydiphenylamine could not be proved unequivocally , but is strongly suggested due to the chemical reactivity? chromatographic behavior, and UV/vis absorption of the compound. Finally, traces of 4-amin ophenol were detected. A reaction scheme is presented explaining the format ion of all identified metabolites via a central sulfenamide cation. Molecul ar orbital calculations for this sulfenamide cation have been performed, co rroborating the proposed reaction mechanisms on the basis of Klopman's gene ralized perturbation theory.