Formation of 4-ethoxy-4'-nitrosodiphenylamine in the reaction of the phenacetin metabolite 4-nitrosophenetol with glutathione

Biol Chem Hoppe Seyler. 1987 Aug;368(8):895-902. doi: 10.1515/bchm3.1987.368.2.895.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemical Phenomena
  • Chemistry
  • Chromatography, High Pressure Liquid
  • Crystallization
  • Erythrocytes / metabolism
  • Glutathione / analysis*
  • Humans
  • In Vitro Techniques
  • Mass Spectrometry
  • Nitroso Compounds / analysis*
  • Phenacetin / analogs & derivatives*
  • Phenacetin / analysis
  • Phenacetin / blood
  • Phenacetin / metabolism*

Substances

  • Nitroso Compounds
  • 4-nitrosophenetole
  • 4-ethoxy-4'-nitrosodiphenylamine
  • Phenacetin
  • Glutathione