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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
(www.genome.org), 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.
For more go to http://www.nature.com/clpt/journal/v88/n3/abs/clpt2010164a.html
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
This is from an industry friendly newsletter
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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
(www.genome.org), 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.
For more go to http://www.nature.com/clpt/journal/v88/n3/abs/clpt2010164a.html
Donald Rumsfeld
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Disclaimer:
The information, facts, and opinions
provided here is not a substitute for professional advice. It only indicates
what JK believes, does, or
would do. Always consult your primary
care physician for any medical advice, diagnosis, and treatment.
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