It is critical for regulating oxidative stress, detoxification and immune function and is most concentrated in the liver, where it is involved in the detoxification process. As paracetamol is almost completely metabolised by the liver, up to 96%, it relies upon abundant levels of glutathione to perform this vital function.
Paracetamol (or acetaminophen) is one of the most extensively used analgesics/antipyretics in the world and, although it’s considered a safe drug when taken as recommended, there is a well established link between paracetamol toxicity and liver failure.
Although hepatic failure and death are uncommon outcomes, paracetamol remains the most important, single cause of acute, severe and sudden onset of hepatic failure in western countries.
One of the mechanisms by which the overuse of paracetamol can cause acute liver failure is its ability to deplete the antioxidant glutathione.
In the presence of paracetamol, the concentration of glutathione decreases by as much as 80-90%. It is shown that once your liver uses more than 30% of your total store of glutathione, you are already in trouble with increasing hepatocyte destruction. This can be as a result from both reduced glutathione stores as well as a toxic metabolite of paracetamol breakdown N-acetyl-p-benzoquinone imine (NAPQI)
These adverse effects experienced as a result of ingesting paracetamol above therapeutic doses is due to how it is detoxified through the liver. Approximately 90% is metabolised to inactive sulfate and glucuronide conjugates that are then excreted in the urine. It’s the metabolism of the remainder, via cytochrome P450, that results in the liver becoming acutely saturated with NAPQI.
In normal conditions NAPQI is immediately bound by intracellular glutathione and eliminated in the urine, but with increased paracetamol doses this greater production of NAPQI further depletes glutathione stores.
Detoxification of NAPQI by conjugation with hepatic glutathione may be further impaired in the setting of malnutrition, recent fasting, an adult weight of under 50kg or advanced cirrhosis. These patients may, therefore, already be at higher risk of paracetamol toxicity.
The sulfhydryl donor N-acetylcysteine (NAC), a precursor for glutathione, speeds up the detoxification of NAPQI and is the only approved agent on the market for treatment of paracetamol overdose.
Thus, early diagnosis and the use of NAC can considerably improve outcomes of patients who present with toxicity.
Article sourced from FX Medicine