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Parallel studies in a large number of healthy volunteers22 using a therapeutic dose of APAP confirmed the considerable variation in CYP-dependent metabolism of APAP to NAPQI, with greater than ten-fold variation amongst ∼200 individuals,22 confirming previous findings.23 These results are consistent with the observation that, whilst an overdose of APAP can cause hepatotoxicity in humans, there is a wide range in sensitivity amongst individuals and many subjects are at relatively low risk.24 When NAPQI was first synthesised and its properties studied it was found to be not only an electrophile but also a strong thiol oxidant.14 This observation gave rise to the question of the relative role played by covalent binding and thiol oxidation in the toxicity of APAP
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