Which metabolite is hepatotoxic in acetaminophen overdose?

• A. Glutathione
• B. Acetaminophen
• C. NAPQI
• D. NAC

Answer: (C)

In an acetaminophen overdose, a reactive metabolite drives liver injury. A portion of acetaminophen is processed by liver enzymes into NAPQI (N-acetyl-p-benzoquinone imine), a highly reactive substance. Normally, NAPQI is quickly neutralized by conjugation with glutathione, forming harmless products that are excreted. But when overdose occurs, glutathione stores get depleted, allowing NAPQI to accumulate and bind to cellular proteins in hepatocytes, triggering oxidative stress and cell death. That’s why the hepatotoxic metabolite is NAPQI.

Glutathione itself is the detoxifying partner that neutralizes NAPQI, not the toxin. Acetaminophen at standard doses isn’t directly hepatotoxic; its danger in overdose comes from the formation of NAPQI. N-acetylcysteine is used to replenish glutathione and aid detoxification, not to act as the toxin.