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 cytoc hromes P450 (P450s) appears to consist of sequential one-electron oxid ation steps rather than of a single concerted transfer of activated ox ygen species from P450 to substrates. 2. In case of the acetanilides p aracetamol (PAR), phenacetin (PHEN), and 4-chloro-acetanilide (4-ClAA) , the first one-electron oxidation step consists of a hydrogen abstrac tion from the acetylamino nitrogen and/or from the other side-chain su bstituent on the aromatic ring. The substrate radicals thus formed del ocalize their spin and the respective reactive centres of the substrat e 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 explai ned. Furthermore, this mechanism is consistent with all available expe rimental data on [O-18]PAR/PHEN, [H-2]PAR, and [C-14]PHEN. 3. The oxid ative metabolic reactions proposed for the acetanilides PAR, PHEN, and 4-ClAA are used to generalize P450-mediated oxidations of these and o ther acetanilides, such as analogues of PAR and 2-N-acetyl-aminofluore ne. 4. A further generalization of the hydrogen abstraction, spin delo calization, radical recombination concept is derived for other aromati c substrates with abstractable hydrogen atoms, notably those with acti vated N-H, 0-H, C-H, or S-H bonds directly attached to the aromatic nu cleus.