Acetaminophen Toxicity

Acetaminophen is one of the most commonly available over-the-counter analgesics, found in Tylenol and other pain relievers. It's possible, however, to ingest too much acetaminophen, and the consequences can be fatal. Acetaminophen overdose remains one of the leading causes of hepatic failure in America, due mainly to accidental overdose as patients are often unaware of the levels of acetaminophen they are ingesting. This very short article should serve as a beginners primer on acetaminophen's mechanism of toxicity.

Acetaminophen itself is not the toxic compound, however, which can also lead to some confusion. The compound responsible for the hepatoxicity associated with acute acetaminophen overdose is a highly reactive metabolite of acetaminophen.

When taking acetaminophen, most of it is metabolized into inactive metabolites in the liver by conjugation with sulfate and glucuronide. However, some of the drug is oxidized by the liver enzyme CYP2E1, which creates a chemical called NAPQI (N-acetyl-p-benzoquinone-imine). This chemical is the culprit behind acetaminophen's hepatoxicity.

With normal doses of acetaminophen, only a small amount of NAPQI is produced, and that amount is quickly and efficiently detoxified in the liver by glutathione. As the amount of acetaminophen ingested increases, however, the load on the sulfate and glucuronide responsible for the metabolism of acetaminophen also increases. Once a certain amount of acetaminophen is ingested, the sulfate and glucuronide can no longer metabolize the acetaminophen, and the rest is oxidized by CYP2E1, which creates an over-abundance of NAPQI. There is enough glutathione in the liver to handle small overdoses, but the more NAPQI that is produced, the greater the chance of all the glutathione being used up.

Once most of the glutathione is used (around 60% or so), no more NAPQI can be detoxified, and it is free to react with the liver cells, which often leads to liver damage and, less frequently, death.

Chemical structure of acetaminophen.

Credit: Ben Mills

Copyright: Public Domain