Glutathione Levels in Human Hepatocytes Exposed to Paracetamol

N-Acetyl-p-aminophenol (acetaminophen, paracetamol) acts above a certain dose as a hepatotoxic in animals and man. The primary cause of cell injury is presumably a metabolite generated by microsomal enzymes, N-acetyl-p-benzoquinone imine, ¹ which depletes cellular glutathione, binds to proteins, ² and causes oxidative stress. ³ There are species differences in the sensitivity of hepatocytes to paracetamol which correlate with the different rates of formation of the reactive metabolite. ⁴ The average single toxic dose of paracetamol causing severe liver damage in man is about 250 mg/kg ⁵ although large interindividual variability exists. This is most likely due to different individual biotransformation rates. ⁵ Because of this and the lack of accurate clinical data, the dose, mechanism and duration of exposure that cause irreversible damage to human liver have not been clearly defined, and it is not definitively known whether paracetamol hepatotoxicity in man is influenced by factors affecting the activity of drug-metabolizing enzymes. ^{6 , 7}