J. Biol. Chem., Vol. 260, Issue 21, 11446-11450, Sep, 1985
Formation of 4-aminophenoxyl free radical from the acetaminophen metabolite N-acetyl-p-benzoquinone imine
V Fischer, PR West, SD Nelson, PJ Harvison and RP Mason
N-Acetyl-p-benzoquinone imine, a hepatic metabolite of acetaminophen, and
its analogue, N-acetyl-3,5-dimethyl-p-benzoquinone imine, were metabolized
by rat liver microsomes and NADPH to their corresponding 4- aminophenoxyl
free radicals. ESR spectra were recorded and unambiguously identified. As
indicated by the purple color and confirmed by UV and mass spectroscopy,
indophenols were formed as final products. The 4-aminophenoxyl free radical
formation could be suppressed by the deacetylase inhibitors, sodium
fluoride and paraoxon. Microsomal incubations of
N-acetyl-2,6-dimethyl-p-benzoquinone imine and NADPH do not result in a
detectable radical concentration; in addition, no indophenol was found.
Substitution of NADPH-cytochrome P- 450 reductase for rat liver microsomes
eliminates the deacetylase activity and results in direct reduction of
N-acetyl-3,5-dimethyl-p- benzoquinone imine to the
N-acetyl-2,6-dimethyl-4-aminophenoxyl free radical. Neither the incubation
of N-acetyl-p-benzoquinone imine nor that of
N-acetyl-2,6-dimethyl-p-benzoquinone imine with NADPH- cytochrome P-450
reductase yielded a detectable concentration of the corresponding phenoxyl
free radical. When starting material that had been exposed to the
atmosphere was used, a previously reported free radical with a splitting
constant of approximately 2 G was formed. This spectrum is identical with
that of the 2,6-dimethyl-p-benzosemiquinone free radical, implying
hydrolysis of the starting material. Neither the N-acetyl-4-aminophenoxyl
nor the N-acetyl-2,6-dimethyl-4-aminophenoxyl radical reduces oxygen to
form superoxide or react with oxygen in any other detectable way.
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