How a Painkiller Turns Liver-killer

Protective effect. Liver cells die (pale areas) when exposed to high doses of acetaminophen (left), but a CAR inhibitor protects against such damage (right).

Overdoses of acetaminophen--the widely used painkiller sold under the brand name Tylenol--can cause severe liver damage. Every year in the United States overdoses of the painkiller cause acute liver failure in as many as 800 people, one-third of whom die as a result. New research helps explain just how acetaminophen harms the liver and may provide a target for treating liver failure due to acetaminophen overdoses.

In the 11 October issue of Science, a team led by David Moore of Baylor College of Medicine in Houston, Texas, identifies a key player in acetaminophen toxicity: the so-called constitutive androstane receptor (CAR). Ordinarily, CAR protects the liver by helping it eliminate foreign chemicals, Moore says. But in some cases it has the opposite effect, creating products that are more toxic than the originals.

A clue that CAR might be involved in acetaminophen toxicity came a few years ago. The drug phenobarbital increases susceptibility to acetaminophen damage because it fosters production of two enzymes in the CYP family that convert acetaminophen to a highly toxic compound called NAPQI. The cell normally eliminates NAPQI by tying it up with a detoxifying molecule called glutathione. But if NAPQI production outstrips the glutathione supply, cell damage occurs. CAR comes into the story because Moore and others found that phenobarbital works through that receptor to enhance CYP enzyme production.

Moore and his colleagues now report that CAR is involved even more directly in acetaminophen toxicity. In normal mice, high doses of acetaminophen increased production of the CYP enzymes, as well as an enzyme called GSTPi that attaches glutathione to NAPQI and other molecules. That could be a double whammy for liver cells--increasing NAPQI production at the same time glutathione supplies are depleted. The animals showed signs of severe liver damage. But in animals in which the CAR gene had been inactivated, the same doses of acetaminophen did not increase production of CYP or GSTPi enzymes, and these animals suffered much less liver damage than normal mice. Moore's team also found that androstanol, a compound that inhibits CAR activity, protected mice against acetaminophen-induced liver damage even after exposure to the painkiller. It provided 100% protection 1 hour later and 50% protection 3 hours later.

Moore and his colleagues "have shown clearly that the receptor is important," says Steven Kliewer, a liver toxicity expert at the University of Texas Southwestern Medical Center in Dallas. Although more work will be needed to show whether CAR inhibitors might be useful treatments for human liver toxicities, Kliewer, for one, is hopeful: "The more we understand about the mechanisms [of liver toxicity], the more opportunities we will have for treatment."

Related sites
Science paper
Moore's site
Basic information about acetaminophen from NIH

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