Metabolic activation and toxicity of acetaminophen and related analogs. A theoretical study

GH Loew and A Goldblum

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.

Volume 27, Issue 3, pp. 375-386, 03/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics