established a direct neurotoxic action by acetaminophen both in vitro and in vivo in rats at doses below those required to produce hepatotoxicity and suggested that this neurotoxicity might be involved in the general toxic syndrome observed during patient acetaminophen overdose and, possibly, when acetaminophen doses in the upper dosing schedule are used, especially if other risk factors (moderate alcohol drinking, fasting, nutritional impairment) are present
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The second peak, mediated at least in part by NOX1, NOX3 and mitochondrial enzymes, results in prolonged signaling through PI3K, NF-B, and AKT
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