Free radicals of acetaminophen: their subsequent reactions and toxicological significance.
The oxidation of acetaminophen to the corresponding phenoxyl free radical and N-acetyl-p-benzoquinone imine by mammalian peroxidases is discussed. The acetaminophen free radical is very reactive--forming dimers, and, ultimately, melanin-like polymeric products. A model compound, leading to more stable metabolites, can be obtained by introduction of methyl groups next to the oxygen, to produce 3,5-dimethylacetaminophen. The electron spin resonance spectrum of this free radical could be completely analyzed. The phenoxyl radical of the dimethyl analog does not form polymers or bind with nucleophiles. N-Acetyl-p-benzoquinone imine, a hepatic metabolite of acetaminophen, and its analog N-acetyl-3,5-dimethyl-p-benzoquinone imine are metabolized by rat liver microsomes and NADPH to their corresponding p-aminophenoxyl free radicals. The p-aminophenoxyl free radical formation could be suppressed by the deacetylase inhibitors sodium fluoride and paraoxon. Substitution of NADPH-cytochrome P-450 reductase for rat liver microsomes eliminates the deacetylase activity and results in the direct reduction of N-acetyl-3,5-dimethyl-p-benzoquinone imine to the 3,5-dimethylacetaminophen phenoxyl free radical. Neither the acetaminophen nor the 3,5-dimethylacetaminophen phenoxyl radical reduces oxygen to form superoxide or reacts with oxygen in any other detectable way.
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D016227:Benzoquinones; D055598:Chemical Phenomena; D056486:Chemical and Drug Induced Liver Injury; D002621:Chemistry; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D006735:Horseradish Peroxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007097:Imines / Q000378:metabolism; D007784:Lactoperoxidase / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D016227:Benzoquinones; D005609:Free Radicals; D007097:Imines; D013481:Superoxides; C042524:3',5'-dimethylacetaminophen; D000082:Acetaminophen; D006861:Hydrogen Peroxide; C022464:prostaglandin hydroperoxidase; D006735:Horseradish Peroxidase; D007784:Lactoperoxidase; D010544:Peroxidases; D009251:NADPH-Ferrihemoprotein Reductase; C028473:N-acetyl-4-benzoquinoneimine