A theoretical study on the metabolic activation of paracetamol by cytochrome P-450: indications for a uniform oxidation mechanism.
The cytochrome P-450 mediated activation of paracetamol (PAR) to the reactive electrophilic intermediate N-acetyl-p-benzoquinone imine (NAPQI) has been studied by use of SV 6-31G ab initio energy calculations and spin distributions. A simplified model for cytochrome P-450 has been used by substituting the proposed biologically active ferric-oxene state of cytochrome P-450 by a singlet oxygen atom. The results indicate that an initial hydrogen abstraction from the phenolic hydroxyl group is favored by 30.1 kcal/mol over an initial hydrogen abstraction from the acetylamino nitrogen atom. Metabolic activation of PAR via primary formation of a phenoxy radical seems the most likely mechanism. The calculated ab initio spin densities indicate that the radical formed by hydrogen abstraction from the phenolic hydroxyl group stays predominantly localized at the phenolic oxygen. A second hydrogen abstraction from the acetylamino nitrogen atom, giving rise to the reactive intermediate NAPQI, is then favored in terms of energy differences. The unpaired electron of the phenoxy radical was found to delocalize only to a small extent toward the carbon atoms at the ortho and para positions relative to the hydroxyl-containing ring carbon, but nevertheless a recombination reaction between a hydroxyl radical and these radicalized carbon atoms at the ortho or para positions could explain the formation of the minor metabolites 3-hydroxy-PAR and p-benzoquinone plus acetamide.
Koymans
L
L
Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
van Lenthe
J H
JH
van de Straat
R
R
Donné-Op den Kelder
G M
GM
Vermeulen
N P
NP
D000081:Acetamides / Q000378:metabolism; D000082:Acetaminophen / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D016227:Benzoquinones / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000494:pharmacology*; D005609:Free Radicals; D007097:Imines / Q000378:metabolism; D008658:Inactivation, Metabolic; D008954:Models, Biological; D009584:Nitrogen / Q000378:metabolism; D010084:Oxidation-Reduction; D013816:Thermodynamics
D000081:Acetamides; D016227:Benzoquinones; D005609:Free Radicals; D007097:Imines; D000082:Acetaminophen; C004532:quinone; C030686:acetamide; D003577:Cytochrome P-450 Enzyme System; C028473:N-acetyl-4-benzoquinoneimine; C027361:3-hydroxyacetaminophen; D009584:Nitrogen