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Non-steroidal anti-inflammatory drug increases liver damage in mice carrying mutant human gene

Alpha-1-antitrypsin deficiency isn't a term that rolls right off the tongue. But people diagnosed with this genetic disorder learn its potential effects well. They know they shouldn't smoke or be around smokers because they are at increased risk for developing emphysema at a young age. In addition, some patients with alpha-1-antitrypsin (AT) deficiency can develop serious liver disease. But predicting which of them are at risk for liver disease is not yet possible.

Now research performed at Washington University School of Medicine in St. Louis sheds light on the mechanisms that contribute to liver disease in alpha-1-AT deficiency patients. Using an experimental mouse model of the disorder, the researchers investigated the effects of a non-steroidal anti-inflammatory drug (NSAID) on liver injury. An estimated 15 to 20 million people in the United States take NSAIDs like ibuprofen and naproxen on a long-term basis.

The findings, published in the October issue of the journal Hepatology, show that the NSAID indomethacin (Indocin), administered at doses typically nontoxic to mice, significantly increased liver damage in the experimental mice.

The mice carried a mutated form of the human alpha-1-AT gene (called the alpha-1-ATZ gene), the most common form of the gene associated with the development of liver disease in people with alpha-1-AT deficiency. Greater expression of the mutant alpha-1-ATZ gene and increased amounts of alpha-1-ATZ protein in the liver accompanied the increase in liver injury in the experimental mice given the NSAID.

"These data demonstrate that environmental factors such as drug administration can affect the development of liver injury in this animal model," says lead author David Rudnick, M.D., Ph.D., assistant professor of pediatrics and of molecular biology and pharmacology. "And they raise the possibility that NSAIDs could have similar effects on gene and protein expression and perhaps on liver injury i
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Contact: Gwen Ericson
ericsong@wustl.edu
314-286-0141
Washington University School of Medicine
15-Nov-2006


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