N-Hydroxyacetaminophen: A Postulated Toxic Metabolite of Acetaminophen

Article abstract of DOI:10.1021/jm00140a014

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*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.