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-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.
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D007700:Kinetics; D008433:Mathematics; D051379:Mice; D051381:Rats
D000082:Acetaminophen; C017372:N-hydroxyacetaminophen