Researchers Make Progress in Understanding Acetaminophen-Caused Liver Toxicity

Baylor College of Medicine researchers have identified a protein known as CAR (constitutive androstane receptor) that regulates liver toxicity caused by the common pain-reliever acetaminophen. Their findings are published in the Oct. 11 issue of the journal Science, and will point the way to new treatments for poisoning with similar compounds.

Acetaminophen is found in Tylenol and many other medications. Advisors to the Food and Drug Administration urged the agency in September 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 David D. Moore, Ph.D., professor of molecular and cell biology at Baylor College of Medicine.

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 if 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.

Others involved in the Baylor studies were graduate student Jun Zhang, and postdoctoral associates Wendong Huang, Steven S. Chua and Ping Wei.

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