Formation of 4-ethoxy-4'-nitrosodiphenylamine in the reaction of the phenacetin metabolite 4-nitrosophenetol with glutathione.
Phenacetin, a constituent of several analgesic and antipyretic formulations has been made responsible for a variety of toxic and carcinogenic actions. 4-Nitrosophenetol, the N-oxydation product of intermediate 4-phenetidine, forms methemoglobin and binds covalently to sulfhydryl groups of proteins and glutathione. In the reaction of 4-nitrosophenetol with glutathione and other thiols an intermediate so-called "semimercaptal" is formed from which N-(thiol-S-yl)-4-phenetidine S-oxide, N-(thiol-S-yl)-4-phenetidine and 4-phenetidine derive. Besides thiol adducts, a yellow compound is formed which was isolated as a pure crystalline product (elemental analysis) and identified by FAB-MS, EI-MS, 13C-, 1H-NMR, and UV-VIS spectroscopy as 4-ethoxy-4'-nitrosodiphenylamine. This nitrosoarene is formed by an unknown mechanism from 4-nitrosophenetol and 4-phenetidine under liberation of ethanol. In human erythrocytes this compound is easily reduced to 4-amino-4'-ethoxydiphenylamine (FAB-MS, EI-MS, 13C-NMR). During the reaction of 4-nitrosophenetol with red cells only traces of 4-ethoxy-4'-nitrosodiphenylamine were formed, whereas up to 10% appeared as the reduction product 4-amino-4'-ethoxydiphenylamine. This latter compound is unstable in red cells and is metabolized further to unidentified products.
Klehr
H
H
Walther-Straub-Institut für Pharmakologie und Toxikologie der Universität München.
Eyer
P
P
Schäfer
W
W
D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000032:analysis*; D006801:Humans; D066298:In Vitro Techniques; D013058:Mass Spectrometry; D009603:Nitroso Compounds / Q000032:analysis*; D010615:Phenacetin / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000378:metabolism*
D009603:Nitroso Compounds; C037221:4-nitrosophenetole; C054076:4-ethoxy-4'-nitrosodiphenylamine; D010615:Phenacetin; D005978:Glutathione