Paracetamol overdose: metabolic pathways
The liver normally conjugates paracetamol with glucuronic acid/sulphate. During an overdose the conjugation system becomes saturated leading to oxidation by P450 mixed function oxidases*. This produces a toxic metabolite (N-acetyl-p-benzoquinone imine or NAPQI)
Normally glutathione acts as a defence mechanism by conjugating NAPQI forming the non-toxic mercapturic acid. If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death. This occurs not only in hepatocytes but also in the renal tubules
N-acetyl cysteine is used in the management of paracetamol overdose as it is a precursor of glutathione and hence can increase hepatic glutathione production
*this explains why there is a lower threshold for treating patients who take P450 inducing medications e.g. phenytoin or rifampicin
Normally glutathione acts as a defence mechanism by conjugating NAPQI forming the non-toxic mercapturic acid. If glutathione stores run-out, the toxin forms covalent bonds with cell proteins, denaturing them and leading to cell death. This occurs not only in hepatocytes but also in the renal tubules
N-acetyl cysteine is used in the management of paracetamol overdose as it is a precursor of glutathione and hence can increase hepatic glutathione production
*this explains why there is a lower threshold for treating patients who take P450 inducing medications e.g. phenytoin or rifampicin