Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

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

17.11.2006
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 in people with alpha-1-AT deficiency."

Approximately 1 in 2,000 individuals has alpha-1-AT deficiency. Rudnick points out that even though alpha-1-AT deficiency is the most common genetic indication for pediatric liver disease and liver transplantation, a study to investigate whether NSAIDs affect human alpha-1-AT patients may not be feasible because of the disorder's relative rarity.

"But I tell my patients with any form of chronic liver injury they should avoid NSAIDs," says Rudnick, a pediatric gastroenterologist at St. Louis Children's Hospital. "The drugs have an established potential hepatotoxicity. I would say alpha-1-AT deficiency liver disease is another example where these drugs should be avoided."

Normally, the liver secretes alpha-1-AT protein into the bloodstream, but the abnormal protein, alpha-1-ATZ, can get "stuck" in liver cells. Liver biopsies of alpha-1-AT deficiency patients reveal that their liver cells have numerous globules containing alpha-1-ATZ protein.

The defective alpha-1-ATZ doesn't reach the lungs, where alpha-1-AT normally regulates enzymes that digest protein. Loss of alpha-1-AT's regulation of protein-digesting enzymes in the lungs can result in tissue damage and emphysema.

In ways not yet entirely understood, accumulation of alpha-1-ATZ in the liver can lead to both liver damage and liver cancer. In the mice carrying the human alpha-1-ATZ gene, the NSAID indomethacin not only caused liver cells to accumulate even more of the abnormal alpha-1-ATZ protein but also to proliferate or multiply faster than usual -- a hallmark of liver response to injury.

People who have alpha-1-AT deficiency vary widely in the severity of liver injury: some patients never have liver problems while others will require a liver transplant before they are two years old. Only 10 to 20 percent of infants with alpha-1-ATZ genes will develop clinically overt liver damage.

"We don't yet know the mechanism accounting for such wide variability in this disorder, but other genetic and environmental factors must contribute," Rudnick says. "The effect of indomethacin on these transgenic mice suggests that NSAIDs may be an example of such an environmental influence."

Gwen Ericson | EurekAlert!
Further information:
http://www.wustl.edu

Further reports about: NSAID Rudnick alpha-1-AT alpha-1-ATZ deficiency liver liver disease

More articles from Life Sciences:

nachricht Historical rainfall levels are significant in carbon emissions from soil
30.05.2017 | University of Texas at Austin

nachricht 3D printer inks from the woods
30.05.2017 | Empa - Eidgenössische Materialprüfungs- und Forschungsanstalt

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New Method of Characterizing Graphene

Scientists have developed a new method of characterizing graphene’s properties without applying disruptive electrical contacts, allowing them to investigate both the resistance and quantum capacitance of graphene and other two-dimensional materials. Researchers from the Swiss Nanoscience Institute and the University of Basel’s Department of Physics reported their findings in the journal Physical Review Applied.

Graphene consists of a single layer of carbon atoms. It is transparent, harder than diamond and stronger than steel, yet flexible, and a significantly better...

Im Focus: Strathclyde-led research develops world's highest gain high-power laser amplifier

The world's highest gain high power laser amplifier - by many orders of magnitude - has been developed in research led at the University of Strathclyde.

The researchers demonstrated the feasibility of using plasma to amplify short laser pulses of picojoule-level energy up to 100 millijoules, which is a 'gain'...

Im Focus: Can the immune system be boosted against Staphylococcus aureus by delivery of messenger RNA?

Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.

Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....

Im Focus: A quantum walk of photons

Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.

The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Marine Conservation: IASS Contributes to UN Ocean Conference in New York on 5-9 June

24.05.2017 | Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

 
Latest News

3D printer inks from the woods

30.05.2017 | Life Sciences

How circadian clocks communicate with each other

30.05.2017 | Life Sciences

Graphene and quantum dots put in motion a CMOS-integrated camera that can see the invisible

30.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>