Paracetamol, liver necrosis metabolites

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Paracetamol is metabolised in the liver, where it is converted to a highly toxic intermediate that is normally detoxified by conjugation with glutathione. In overdose, this detoxification mechanism is overwhelmed and the free toxic metabolite causes hepatitis and necrosis, which can prove fatal. 

---