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Acetaminophen (APAP) overdose in most species is associated with hepatotoxicity due to covalent binding of the reactive metabolite N-acetyl- p-benzoquinoneimine (NAPQI) to hepatocellular proteins. Dogs and cats are unique in that acetaminophen overdose primarily causes methemoglobinemia and hemolysis. It has been proposed that NAPQI is the responsible reactive intermediate in dogs and cats but it does not have the chemical or pharmacokinetic characteristics that would favor methemoglobin formation. Our hypothesis is that the deficiency of N-acetyltransferase (NAT) activity in dogs and cats allows accumulation of another acetaminophen metabolite, para-aminophenol (PAP) that then induces methemoglobinemia. We have demonstrated that dogs, cats, mice and rats can all deacetylate APAP to PAP in vitro with no significant difference between species. Dogs were unable to acetylate PAP to APAP in vitro while feline acetylation of PAP in vitro was significantly less than rats and mice (feline Vmax=0.088 0.004 nmol/mg prot/min, apparent rat Vmax=0.63 0.027 nmol/mg prot/min and apparent wildtype mouse Vmax=1.42 0.1 nmol/mg prot/min; P