Featured Research

from universities, journals, and other organizations

Non-steroidal Anti-inflammatory Drug Increases Liver Damage In Mice Carrying Mutant Human Gene

Date:
November 16, 2006
Source:
Washington University School of Medicine
Summary:
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. People with alpha-1-deficiency have a genetic mutation that can lead to emphysema at an early age and to liver damage. Using an experimental mouse model of the disorder, the researchers investigated the effects of a non-steroidal anti-inflammatory drug on liver injury.

The large globules in the liver cells on the left are characteristic of alpha-1-antitrypsin deficiency. The image on the right shows normal liver cells.
Credit: Image courtesy of Washington University School of Medicine

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."

Citation: Rudnick DA, Shikapwashya O, Blomenkamp K, Techman JH. Indomethacin increases liver damage in a murine model of liver injury from alpha-1-antitrypsin deficiency. Hepatology 2006;44(4):976-982.


Story Source:

The above story is based on materials provided by Washington University School of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

Washington University School of Medicine. "Non-steroidal Anti-inflammatory Drug Increases Liver Damage In Mice Carrying Mutant Human Gene." ScienceDaily. ScienceDaily, 16 November 2006. <www.sciencedaily.com/releases/2006/11/061116082720.htm>.
Washington University School of Medicine. (2006, November 16). Non-steroidal Anti-inflammatory Drug Increases Liver Damage In Mice Carrying Mutant Human Gene. ScienceDaily. Retrieved August 22, 2014 from www.sciencedaily.com/releases/2006/11/061116082720.htm
Washington University School of Medicine. "Non-steroidal Anti-inflammatory Drug Increases Liver Damage In Mice Carrying Mutant Human Gene." ScienceDaily. www.sciencedaily.com/releases/2006/11/061116082720.htm (accessed August 22, 2014).

Share This




More Health & Medicine News

Friday, August 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Drug Used To Treat 'Ebola's Cousin' Shows Promise

Drug Used To Treat 'Ebola's Cousin' Shows Promise

Newsy (Aug. 21, 2014) An experimental drug used to treat Marburg virus in rhesus monkeys could give new insight into a similar treatment for Ebola. Video provided by Newsy
Powered by NewsLook.com
Two US Ebola Patients Leave Hospital Free of the Disease

Two US Ebola Patients Leave Hospital Free of the Disease

AFP (Aug. 21, 2014) Two American missionaries who were sickened with Ebola while working in Liberia and were treated with an experimental drug are doing better and have left the hospital, doctors say on August 21, 2014. Duration: 01:05 Video provided by AFP
Powered by NewsLook.com
Cadavers, a Teen, and a Medical School Dream

Cadavers, a Teen, and a Medical School Dream

AP (Aug. 21, 2014) Contains graphic content. He's only 17. But Johntrell Bowles has wanted to be a doctor from a young age, despite the odds against him. He was recently the youngest participant in a cadaver program at the Indiana University NW medical school. (Aug. 21) Video provided by AP
Powered by NewsLook.com
American Ebola Patients Released: What Cured Them?

American Ebola Patients Released: What Cured Them?

Newsy (Aug. 21, 2014) It's unclear whether the American Ebola patients' recoveries can be attributed to an experimental drug or early detection and good medical care. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins