RT Journal Article
SR Electronic
T1 Microsomal <em>N</em>-Hydroxylation of <em>p</em>-Chloroacetanilide
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 462
OP 469
VO 11
IS 4
A1 HINSON, J. A.
A1 MITCHELL, J. R.
A1 JOLLOW, D. J.
YR 1975
UL http://molpharm.aspetjournals.org/content/11/4/462.abstract
AB Microsomes obtained from hamster liver catalyze the N-hydroxylation of p-chloroacetanilide. The reaction requires NADPH and is inhibited by a carbon monoxide—oxygen atmosphere, indicating that it is catalyzed by a cytochrome P-450-dependent mixedfunction oxidase. The enzyme activity in hamster microsomes is induced by prior treatment of the animals with 3-methylcholanthrene but not with phenobarbital, and is inhibited by piperonyl butoxide. The yield of N-hydroxy metabolite is enhanced by the presence of sodium fluoride in the reaction mixture; this effect appears to be due to a selective stimulation of N-hydroxylation and not to an inhibition of deacetylation of N-hydroxy-p-chloroacetanilide. These results demonstrate that the microsomal enzyme system catalyzing the N-hydroxylation of p-chloroacetanilide and the formation of the arylating, hepatotoxic metabolite of acetaminophen share many distinctive characteristics. The close correlation between these systems supports the hypothesis that the hepatotoxic metabolite of acetaminophen results from initial N-hydroxylation followed by immediate loss of water to yield the chemically reactive acetimidoquinone.