N-Hydroxyacetaminophen: a postulated toxic metabolite of acetaminophen

The decomposition of N-hydroxyacetaminophen has been shown to occur via an initial first-order dehydration step to N-acetyl-p-benzoquinone imine with a rate constant at pH 7.6 of 8.66 x 10(-3) min-1 and a half-life of 80 min. This is followed by a complex reaction between the quinone imine and the N...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1981-08, Vol.24 (8), p.988-993
Main Authors: Calder, Ian C, Hart, Sandra J, Healey, Kevin, Ham, Kathryn N
Format: Article
Language:English
Subjects:
Acetaminophen - analogs & derivatives
Acetaminophen - metabolism
Acetaminophen - toxicity
Animals
Biotransformation
Kinetics
Mathematics
Mice
Rats
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Summary:The decomposition of N-hydroxyacetaminophen has been shown to occur via an initial first-order dehydration step to N-acetyl-p-benzoquinone imine with a rate constant at pH 7.6 of 8.66 x 10(-3) min-1 and a half-life of 80 min. This is followed by a complex reaction between the quinone imine and the N-hydroxy compound to ultimately yield p-nitrosophenol and acetaminophen. The glucuronide and sulfate conjugates of N-hydroxyacetaminophen have been observed as urinary metabolites of N-hydroxyacetaminophen. No N-hydroxylated metabolites were found among the metabolites of acetaminophen. These results have been interpreted to show that N-hydroxyacetaminophen is not a metabolite of acetaminophen. It is proposed that the hepatotoxicity and nephrotoxicity of acetaminophen are mediated by a direct oxidation of acetaminophen to the toxic reactive intermediate N-acetyl-p-benzoquinone imine by the cytochrome P450 dependent mixed-function oxidase system.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00140a014