Metabolic activation and toxicity of acetaminophen and related analogs. A theoretical study.
Reaction thermodynamics have been calculated for an oxene model for cytochrome P-450 oxidations of four related arylamines: aniline, p-hydroxyaniline, acetanilide, and acetaminophen, by both radical and nonradical mechanisms, using a semiempirical molecular orbital method (modified neglect of differential overlap). The results indicate that for both p-hydroxyaniline and acetaminophen, a recently proposed peroxidase-like mechanism leading directly to p-benzoquinoneimines via radical intermediates is thermodynamically favored over N-hydroxylamine formation by H abstraction or addition rearrangement. These studies also provide a detailed characterization of three candidate species for the toxic reactive intermediate of acetaminophen: 1) p-benzoquinoneimines, 2) the radical intermediate formed by H abstraction from the nitrogen, and 3) the radical intermediate formed by H abstraction from the phenol. Calculated electron and spin densities indicate that the radical formed by H abstraction from the phenol oxygen does not remain localized on the oxygen, but is primarily a semiquinone aryl radical with significant unpaired spin density on the ring carbon atoms, particularly on C-3 and C-5. This result is consistent with the hyperfine splitting pattern observed for a transient radical species in a hydroxyl radical-mediated chemical oxidation of acetaminophen. The radical formed by H abstraction from the nitrogen also delocalizes on the ring carbons, but to a lesser extent and at the 2- and 4-positions. A closed shell mechanism of N oxidation of arylamines appears to lead directly to the hydroxylamines with less likelihood of precursor reactive intermediates. Toxic species could then be formed by loss of H2O from the hydroxylamines.
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D000082:Acetaminophen / Q000378:metabolism*; D000083:Acetanilides / Q000378:metabolism; D000627:Aminophenols / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D008433:Mathematics; D008954:Models, Biological; D008956:Models, Chemical; D013816:Thermodynamics
D000083:Acetanilides; D000627:Aminophenols; D000814:Aniline Compounds; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System