Acetaminophen Toxicity

Acetaminophen (paracetamol, Tylenol) is one of the most commonly used over-the-counter analgesics and antipyretics worldwide, and acetaminophen overdose is the leading cause of acute liver failure in North America. At therapeutic doses (maximum 4 grams per day in healthy adults, 2 grams per day in patients with liver disease), approximately 90% of acetaminophen is metabolized in the liver through glucuronidation and sulfation (phase II conjugation reactions), producing non-toxic metabolites excreted by the kidneys. Approximately 5-10% is oxidized by the cytochrome P450 enzyme system (primarily CYP2E1) into a highly reactive toxic intermediate called N-acetyl-p-benzoquinone imine (NAPQI). Under normal circumstances, NAPQI is immediately detoxified by conjugation with glutathione (an endogenous antioxidant) to form non-toxic mercapturic acid and cysteine conjugates. In overdose situations, the glucuronidation and sulfation pathways become saturated, shunting a larger proportion of acetaminophen through the CYP2E1 pathway. This generates massive amounts of NAPQI that overwhelm the available glutathione stores. When glutathione is depleted below approximately 30% of normal levels, free NAPQI accumulates and binds covalently to hepatocyte proteins and mitochondrial structures, causing oxidative stress, mitochondrial dysfunction, and hepatocellular necrosis. The...