Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New paradigm identifies gene responsible for acetaminophen-induced liver injury

06.05.2009
Acetaminophen (Tylenol and generics) is one of the most commonly used over-the-counter drugs in the United States. While generally safe, acetaminophen is known to cause severe liver injury if taken in high doses.

But likely due to genetics, even the recommended dose can induce serious liver damage in a significant number of people. In a study published online in Genome Research, scientists have found a genetic marker linked to the risk of acetaminophen-induced liver injury, using a strategy that will help develop safer drugs in the future.

Acetaminophen is considered safe over long-term use, but recent studies have indicated that even over a relatively short period, the maximum allowable dose can induce elevated levels of the liver enzyme ALT in blood serum in approximately one third of healthy individuals, suggesting possible liver injury.

It is possible that if given high doses, many of these individuals would be susceptible to acute liver failure. There is likely to be a genetic predisposition, but finding the variants by scanning human subjects alone can be very difficult, requiring large studies with many participants. But with a little help from mice, researchers can overcome these experimental hurdles.

In this study, a team of researchers led by Dr. David Threadgill of North Carolina State University utilized mouse genetics to aid the search for candidate genes linked to acetaminophen-induced liver injury in humans. "We approached the study from the perspective that drugs are used in very heterogeneous patient populations, and that drug-induced toxicities are likely the result of a person's genetic makeup," Threadgill explained. The group used a genetically diverse population of mice to model human genetic variation, taking advantage of the known genetic differences in these strains to find genes linked to variable responses to acetaminophen treatment.

Once Threadgill and colleagues narrowed their search to a few candidate genes in mouse, they sequenced the genetic code of the counterparts of the same genes in human patients exhibiting elevated levels of serum ALT in response to acetaminophen. They found that a single letter change to the DNA sequence in one of these candidate genes, called CD44, is significantly associated with elevated serum ALT in these patients. While the role of this gene in liver toxicity is not yet known, CD44 could serve as a potentially useful marker to identify people at risk for acetaminophen-induced liver damage.

Threadgill noted that in addition to the identification of a gene linked to acetaminophen-induced liver injury, this study has broader implications for drug testing, as up until now, genetic differences in humans has not been considered in pre-clinical tests using animal models. "If genetic differences are included in early safety testing, more accurate predictions of clinical response will be obtained," said Threadgill. "The end result will be safer drugs."

Scientists from the University of North Carolina (Chapel Hill, NC), the Genomics Institute of the Novartis Research Foundation (San Diego, CA), the Jackson Laboratory (Bar Harbor, ME), the National Institute of Environmental Health Sciences (Research Triangle Park, NC), Verto Institute Research Laboratories (New Brunswick, NJ), the Cancer Institute of New Jersey (New Brunswick, NJ), Purdue Pharma (Stamford, CT), and North Carolina State University (Raleigh, NC) contributed to this study.

This work was supported by the National Institutes of Health and the Environmental Protection Agency.

Media contacts: David Threadgill, Ph.D. (threadgill@ncsu.edu, +1-919-515-2292) is available for more information.

Interested reporters may obtain copies of the manuscript from Robert Majovski, Ph.D., Assistant Editor, Genome Research (majovski@cshl.edu).

About the article: The manuscript will be published online ahead of print on May 5, 2009. Its full citation is as follows: Harrill, A.H., Watkins, P.B., Su, S., Ross, P.K., Harbourt, D.E., Stylianou, I.M., Boorman, G.A., Russo, M.W., Sackler, R.S., Harris, S.C., Contractor, T., Wiltshire, T., Rusyn, I., and Threadgill, D.W. Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans. Genome Res. doi:10.1101/gr.090241.108.

About Genome Research:

Launched in 1995, Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.

About Cold Spring Harbor Laboratory Press:

Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.

Genome Research issues press releases to highlight significant research studies that are published in the journal.

Robert Majovski | EurekAlert!
Further information:
http://www.cshl.edu
http://www.genome.org

More articles from Life Sciences:

nachricht What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Simple processing technique could cut cost of organic PV and wearable electronics

06.12.2016 | Materials Sciences

3-D printed kidney phantoms aid nuclear medicine dosing calibration

06.12.2016 | Medical Engineering

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>