Which statement correctly describes the cause of acetaminophen overdose?

• A. Acetaminophen is excreted unchanged by the kidneys
• B. Acetaminophen increases cytochrome P450 inhibition
• C. Acetaminophen is converted to a toxic metabolite by cytochrome P450
• D. Acetaminophen reduces liver glutathione stores directly

Answer: (C)

In an acetaminophen overdose, the danger comes from a toxic metabolite produced when the drug is processed by the liver's cytochrome P450 system. Most acetaminophen is safely cleared through conjugation, but a portion is oxidized by CYP enzymes to NAPQI, a reactive intermediate. Under normal dosing, NAPQI is quickly neutralized by glutathione. When overdose occurs, glutathione stores become depleted faster than they can be replenished, so NAPQI accumulates and binds to cellular proteins, leading to liver cell injury and potential liver failure. This is why the mechanism described—acetaminophen being converted to a toxic metabolite by cytochrome P450—best explains the cause of overdose. The drug does not primarily inhibit cytochrome P450, and it does not directly wipe out glutathione; rather, it creates a toxic metabolite that overwhelms and depletes glutathione’s detoxifying capacity. Clinically, N-acetylcysteine can replenish glutathione and help detoxify NAPQI.