Free-radical metabolites of acetaminophen and a dimethylated derivative.
The oxidation of acetaminophen (4'-hydroxyacetanilide) to the corresponding N-acetyl-p-benzoquinone imines by plant and mammalian peroxidases is discussed. The acetaminophen free radical (N-acetyl-4-aminophenoxyl) has been reported as an intermediate. It is very reactive and forms melanin-like polymeric products. Application of a fast-flow system makes it possible to detect the transient species and clearly distinguish it from persistent paramagnetic melanin polymers. A model system, leading to more stable metabolites, can be obtained by introduction of methyl groups next to the oxygen, 3',5'-dimethylacetaminophen (3',5'-dimethyl-4'-hydroxyacetanilide). The ESR spectrum of the free radical formed could be completely analyzed and confirmed by deuterium substitution. The data are consistent with the assignment to a phenoxyl free radical (N-acetyl-2,6-dimethyl-4-amino-phenoxyl). Its formation is discussed in terms of substrate, hydrogen peroxide and enzyme concentration dependence. It is believed to be formed via a direct one-electron oxidation of 3',5'-dimethyl-4'-hydroxy-acetanilide. The radical does not form polymers or react with nucleophiles. Its redox behavior is discussed. The possible reaction of these phenoxyl free radicals with oxygen is thought to be negligible.
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D005609:Free Radicals; D006735:Horseradish Peroxidase / Q000378:metabolism; D007700:Kinetics; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism
D005609:Free Radicals; D000082:Acetaminophen; D006735:Horseradish Peroxidase; D010544:Peroxidases