Stable free radical and benzoquinone imine metabolites of an acetaminophen analogue.
The enzymatic oxidation of the acetaminophen analogue 3',5'-dimethyl-4'-hydroxyacetanilide (3',5'-dimethylacetaminophen) with the horseradish peroxidase/hydrogen peroxide system forms a phenoxyl free radical metabolite. The structure of this free radical is established by a complete analysis of the ESR spectrum and confirmed by deuterium isotope substitution. Concomitant with phenoxyl radical formation, N-acetyl-3,5-dimethyl-p-benzoquinone imine was detected by optical spectroscopy. The free radical is also formed by comproportionation in solutions of the quinone imine containing added 3',5'-dimethylacetaminophen. In contrast to acetaminophen, the imine and radical metabolites are stable and can be detected without resort to rapid-mixing techniques. Factors leading to the increased stability of these metabolites relative to those formed from acetaminophen are discussed in terms of the toxicity of acetaminophen.
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism; D016227:Benzoquinones; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006735:Horseradish Peroxidase / Q000378:metabolism*; D006861:Hydrogen Peroxide; D007097:Imines / Q000032:analysis / Q000378:metabolism*; D007202:Indicators and Reagents; D007700:Kinetics; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*
D016227:Benzoquinones; D005609:Free Radicals; D007097:Imines; D007202:Indicators and Reagents; C042524:3',5'-dimethylacetaminophen; D000082:Acetaminophen; C040069:N-acetyl-3,5-dimethyl-4-benzoquinone imine; D006861:Hydrogen Peroxide; D006735:Horseradish Peroxidase; D010544:Peroxidases