On the chemistry of the reaction between N-acetylcysteine and 4-[(4-ethoxyphenyl)imino]-2,5-cyclohexadien-1-one, a 4-ethoxyaniline metabolite formed during peroxidase reactions.
4-Ethoxyaniline (p-phenetidine) is oxidized by peroxidases to form several products, one of which is 4-[(4-ethoxyphenyl)imino]-2,5-cyclohexadien-1-one (1). This compound reacts with N-acetylcysteine (NAC) in methanol-phosphate buffers, generating at least four different products. Four major products, 4-[(4-ethoxyphenyl)amino]phenol (2), 3-(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)amino]phenol (3), 2,5-bis(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)-amino]phenol (4), and 2,5-bis(N-acetylcystein-S-yl)-4-[(4-ethoxyphenyl)imino]-2,5- cyclohexadien-1-one (5), were isolated and identified by NMR spectroscopy and mass spectrometry. The relative ratio between the formed products depends on the pH, the concentration of NAC, and the reaction time. Compound 2, which is the reduced form of 1, was the dominating product when the reaction took place at pH 3, whereas formation of the mono conjugate (3) was more extensive at a neutral pH. Under alkaline conditions 2 and 3 were oxidized by 1 or O2. The oxidized form of 3 was subsequently attacked by a second molecule of NAC, generating the bis conjugate (4). Unless an excess of NAC was present, compound 4 underwent rapid oxidation to 5. Quinone imines, like 1, generating mono conjugates, which are more reactive than the quinone imines per se, are likely to inflict an increased toxic potential and an increased stress on the endogenous thiol pool, resulting in an overall greater toxicity.
Lindqvist
T
T
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden.
Kenne
L
L
Lindeke
B
B
D000111:Acetylcysteine / Q000378:metabolism*; D016227:Benzoquinones / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000494:pharmacology*; D010628:Phenetidine / Q000378:metabolism*
D016227:Benzoquinones; D010628:Phenetidine; C050118:4-(ethoxyphenyl)-4-benzoquinone imine; D010544:Peroxidases; D005978:Glutathione; D000111:Acetylcysteine