Protein Contributes to Acetaminophen Toxicity

A recent study has shown that a protein known as CAR (constitutive androstane receptor) regulates liver toxicity caused by the common pain-reliever acetaminophen. The study appeared in the October 11, 2002, issue of Science.

Ingestion of acetaminophen stimulates the liver to produce small amounts of potentially harmful NAPQI (N-acetyl-p-benzoquinone imine). Normally, NAPQI is quickly neutralized by glutathione in the liver. However, an overdose of acetaminophen can cause depletion of glutathione, which leads to severe toxic effects on the liver.

To study this phenomenon, researchers from Baylor College of Medicine (Houston, TX, USA) developed a mouse line that lacked the CAR gene. "We found out that high doses of acetaminophen activate CAR, and that CAR then activates target genes that increase toxicity,” explained Dr. David D. Moore, professor of molecular and cell biology at Baylor College of Medicine. "This generates a vicious cycle in which acetaminophen actually worsens its own toxicity.”

Due to the absence of this cycle, mice without CAR are partially resistant to high doses of acetaminophen. Dr. Moore continued, "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.”



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Baylor College of Medicine