Acetaminophen is found in Tylenol and many other medications. Just last month, advisors to the U.S. Food and Drug Administration urged the agency to require a stronger warning label on such products.
"Our work explains an important, but unexpected, component of acetaminophen toxicity and adds a new mechanism to the process. It also suggests a new approach to treating hepatotoxicity," said Dr. David D. Moore, professor of molecular and cell biology at Baylor College of Medicine.
Others involved in the Baylor studies were Jun Zhang, a graduate student, and Drs. Wendong Huang, Steven S. Chua and Ping Wei. When a person takes acetaminophen, the liver produces small amounts of a potentially harmful compound called NAPQI (N-acetyl-p-benzoquinone imine). Normally, the liver uses another chemical called glutathione to quickly neutralize NAPQI.
"The problem occurs when you run out of glutathione," said Moore.
An overdose of acetaminophen can cause depletion of glutathione and land a person in the hospital. "Acetaminophen toxicity is the number one cause of hospital admission for liver failure in the United States," he said.
CAR is a receptor that regulates the response of the liver to drugs and other foreign compounds. When it is activated, the liver increases its ability to modify such compounds and eliminate them from the body. This is normally a protective response. In some cases, however, it can also result in harmful effects, for example by increasing the production of toxic byproducts like NAPQI.
Using a mouse bred to lack CAR, Moore and his co-workers showed that the receptor was critical to the medication's toxicity.
"We found out that high doses of acetaminophen activate CAR, and that CAR then activates target genes that increase toxicity," said Moore. "This generates a vicious cycle in which acetaminophen actually worsens its own toxicity. Because of the absence of this cycle, mice without CAR are partially resistant to high doses of acetaminophen."
When mice that have CAR were given a drug called androstanol, which reverses the receptor's activity, they were even more resistant to toxic effects of acetaminophen. Androstanol could even protect the liver if it was given an hour after a high does of acetaminophen. However, mice that lacked CAR showed no protective effect.
The current treatment for acetaminophen overdose relies on a compound that replenishes the glutathione in the liver. This treatment is effective, provided it is given in time.
Blocking CAR "would provide a completely different approach to acetaminophen toxicity and possibly to the toxicity of other agents for which no drug treatment is currently available," said Moore.
Unfortunately, there is no drug yet that efficiently blocks the human form of CAR. Studies to identify such an inhibitor are under way.