Acetaminophen, also known as paracetamol, is a widely used painkiller and antipyretic fever reducer . It is primarily metabolized in the liver by various enzymes. The liver metabolizes acetaminophen through three main pathways: glucuronidation, sulfation, and oxidation.1. Glucuronidation: This is the primary metabolic pathway for acetaminophen, accounting for about 50-70% of the drug's metabolism. In this process, the enzyme UDP-glucuronosyltransferase UGT catalyzes the conjugation of acetaminophen with glucuronic acid, forming acetaminophen glucuronide. This metabolite is water-soluble and is excreted through the kidneys into the urine.2. Sulfation: This pathway accounts for about 25-35% of acetaminophen metabolism. The enzyme sulfotransferase SULT catalyzes the conjugation of acetaminophen with sulfate, forming acetaminophen sulfate. This metabolite is also water-soluble and is excreted through the kidneys into the urine.3. Oxidation: This pathway is responsible for a smaller portion of acetaminophen metabolism about 5-10% . The enzyme cytochrome P450, primarily CYP2E1, catalyzes the oxidation of acetaminophen to form a highly reactive and toxic intermediate metabolite called N-acetyl-p-benzoquinone imine NAPQI . Under normal circumstances, NAPQI is rapidly detoxified by conjugation with glutathione, a natural antioxidant present in the liver, forming a non-toxic, water-soluble metabolite that is excreted through the kidneys into the urine.However, when acetaminophen is taken in excessive amounts or when the liver's glutathione reserves are depleted, NAPQI accumulates in the liver. This can lead to oxidative stress, lipid peroxidation, and covalent binding of NAPQI to cellular proteins, causing hepatocyte liver cell damage, inflammation, and ultimately, liver failure. This is the primary reason why acetaminophen overdose is a leading cause of acute liver failure.In addition to liver damage, high levels of NAPQI can also cause damage to other organs, such as the kidneys. Acetaminophen-induced nephrotoxicity kidney damage can result from the direct toxic effects of NAPQI or from the secondary effects of liver damage, such as reduced blood flow to the kidneys.To mitigate the risk of liver damage from acetaminophen, it is essential to follow the recommended dosage guidelines and avoid combining the drug with other substances that can increase the activity of CYP2E1, such as alcohol. In cases of acetaminophen overdose, the administration of N-acetylcysteine NAC can help replenish glutathione levels and prevent liver damage.