Generalized cytochrome P450-mediated oxidation and oxygenation reactions in aromatic substrates with activated N-H, O-H, C-H, or S-H substituents.
1. The general mechanism of metabolic oxidation of substrates by cytochromes P450 (P450s) appears to consist of sequential one-electron oxidation steps rather than of a single concerted transfer of activated oxygen species from P450 to substrates. 2. In case of the acetanilides paracetamol (PAR), phenacetin (PHEN), and 4-chloro-acetanilide (4-CLAA), the first one-electron oxidation step consists of a hydrogen abstraction from the acetylamino nitrogen and/or from the other side-chain substituent on the aromatic ring. The substrate radicals thus formed delocalize their spin and the respective reactive centres of the substrate radical recombine with a P450 iron-bound hydroxyl radical to either yield oxygenated metabolites, or undergo a second hydrogen abstraction forming dehydrogenated products. By this mechanism, the formation of all known oxidative metabolites of PAR, PHEN, and 4-ClAA can be explained. Furthermore, this mechanism is consistent with all available experimental data on [18O]PAR/PHEN, [2H]PAR, and [14C]PHEN. 3. The oxidative metabolic reactions proposed for the acetanilides PAR, PHEN, and 4-ClAA are used to generalize P450-mediated oxidations of these and other acetanilides, such as analogues of PAR and 2-N-acetyl-aminofluorene. 4. A further generalization of the hydrogen abstraction, spin delocalization, radical recombination concept is derived for other aromatic substrates with abstractable hydrogen atoms, notably those with activated N-H, O-H, C-H, or S-H bonds directly attached to the aromatic nucleus.
Koymans
L
L
Department of Pharmacochemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Donné-Op den Kelder
G M
GM
te Koppele
J M
JM
Vermeulen
N P
NP
D000082:Acetaminophen / Q000378:metabolism; D000083:Acetanilides / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D010084:Oxidation-Reduction; D010615:Phenacetin / Q000378:metabolism
D000083:Acetanilides; D000082:Acetaminophen; C012241:4-chloroacetanilide; D003577:Cytochrome P-450 Enzyme System; D010615:Phenacetin