posted on 2017-05-05, 00:00authored byRomina Castañeda-Arriaga, Annia Galano
Several
chemical routes related to the toxicity of paracetamol
(APAP, also known as acetaminophen), its analogue N-acetyl-m-aminophenol (AMAP), and their deacetylated
derivatives, were investigated using the density functional theory.
It was found that AMAP is more resilient to chemical oxidation than
APAP. The chemical degradation of AMAP into radical intermediates
is predicted to be significant only when it is induced by strong oxidants.
This might explain the apparent contradictions among experimental
evidence regarding AMAP toxicity. All of the investigated species
are incapable of oxidizing DNA, but they can damage lipids by H atom
transfer (HAT) from the bis-allylic site, with the phenoxyl radical
of AMAP being the most threatening to the lipids’ chemical
integrity. Regarding protein damage, Cys residues were identified
as the most likely targets. The damage in this case may involve two
different routes: (i) HAT from the thiol site by phenoxyl radicals
and (ii) protein arylation by the quinone imine (QI) derivatives.
Both are not only thermochemically viable, but also are very fast
reactions. According to the mechanism identified here as the most
likely one for protein arylation, a rather large concentration of
QI would be necessary for this damage to be significant. This might
explain why APAP is nontoxic in therapeutic doses, while overdoses
can result in hepatic toxicity. In addition, the QI derived from both
APAP and AMAP were found to be capable of inflicting this kind of
damage. In addition, it is proposed that they might increase •OH production via the Fenton reaction, which would
contribute to their toxicity.