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Scientists Find How Painkiller Damages Liver

Discover molecular mechanism acetaminophen causes

THURSDAY, Oct. 10, 2002 (HealthDayNews) -- Researchers say they have found a surprising mechanism by which acetaminophen causes liver damage and they are close to a better treatment for the overdoses that are the leading cause of liver failure.

Until now, the accepted picture has been that an overdose of the widely used painkiller sets off a series of molecular events that cause overproduction of a molecule called NAPQI that attacks liver cells, says David D. Moore, a professor of molecular and cell biology at Baylor College of Medicine. He is the leader of the group reporting the finding in tomorrow's issue of Science.

"What we add is that acetaminophen induces its own toxicity," Moore says. His research centers on a molecule called CAR, which regulates the response of the liver to a number of drugs. Working with mice, Moore and his colleagues show that high doses of acetaminophen activate CAR, increasing production of toxic substances.

The Baylor researchers have found a molecule, androstanol, which can block CAR activity if given within an hour of an acetaminophen overdose -- but only in mice. "CAR is different in mouse and humans," Moore says, different enough so that the treatment that works in rodents doesn't affect human liver cells. Research for an androstanol-like molecule that will be effective in humans is under way, he says.

"We haven't found anything very strong yet, but we are confident that we will be able to identify something," Moore says.

Acetaminophen overdoses now are treated with a compound that increases the body's production of glutathione, a naturally occurring molecule that neutralizes NAPQ1. 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 available," Moore says.

The discovery "provides a very clear and very elegant mechanism for how this damage occurs," says Steven Kliewer, a professor of molecular biology at the University of Texas Southwestern Medical Center who has done research in the field. "The more we understand about the mechanism, the better people will be able to treat it."

Until now, Kliewer says, "I don't think anybody has had a very good handle on how this happens."

The background to the research is concern about the possible dangers of acetaminophen, which is best known by the brand name Tylenol but which is found in more than 100 over-the-counter products. Last month, an advisory committee to the U. S. Food and Drug Administration (FDA) recommended a stronger warning on products containing acetaminophen, and there have been some calls for changing its over-the-counter status. The FDA has not yet acted.

"An important part of the debate is that acetaminophen never received regulatory approval, since it was already on the market when the FDA began to give approvals," Moore says. "Some people think it would be reasonable for it to go through the approval process."

If acetaminophen is taken in the recommended dose, there is no danger, Moore says. One problem is that many people are not aware that a specific product they are using contains acetaminophen, he says.

What To Do

Detailed information about acetaminophen is available from the National Library of Medicine. Learn about its potential dangers from eMedicine.

SOURCES: David D. Moore, Ph.D., professor, molecular and cell biology, Baylor College of Medicine, Houston; Steven Kliewer, Ph.D., professor, molecular biology, University of Texas Southwestern Medical Center, Dallas; Oct. 11, 2002, Science
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