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The Metabolism of Acetaminophen and the Synthesis of Glutathione

The primary pathways for acetaminophen metabolism (Panel A) are glucuronidation and sulfation to nontoxic metabolites. Approximately 5% of a therapeutic dose is metabolized by cytochrome P450 2E1 to the electrophile N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is extremely toxic to the liver. Ordinarily, NAPQI is rapidly detoxified by interaction with glutathione to form cysteine and mercapturic acid conjugates. If glutathione is depleted, NAPQI interacts with various macromolecules, leading to hepatocyte injury and death. Glutathione is synthesized from the amino acids cysteine, glutamate, and glycine by means of the pathway shown in Panel B. Glutamate and glycine are present in abundance in hepatocytes; the availability of cysteine is the rate-limiting factor in glutathione synthesis. However, cysteine itself is not well absorbed after oral administration. Acetylcysteine, in contrast, is readily absorbed and rapidly enters cells, where it is hydrolyzed to cysteine, thus providing the limiting substrate for glutathione synthesis.

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