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Using Gene Expression for Early Detection of Acetaminophen Overdose

By Robin Mackar
December 2007

Paules spoke at the December 2006 National Center for Toxicogenomics conference where he presented preliminary findings of microarray detection of acetaminophen overdose in a lecture titled
Paules spoke at the December 2006 National Center for Toxicogenomics conference where he presented preliminary findings of microarray detection of acetaminophen overdose in a lecture titled "Linking Phenotype Endpoints with Genomics to Identify Signatures Predictive of Adverse Health Effects." (Photo courtesy of Steve McCaw)
Tennant was the director of the National Center for Toxicogenomics, which helped pioneer the use of microarray gene expression in predictive toxicology.
Tennant was the director of the National Center for Toxicogenomics, which helped pioneer the use of microarray gene expression in predictive toxicology. (Photo courtesy of Steve McCaw)

In a new study, researchers report they could detect toxic levels of acetaminophen in laboratory animals by analyzing gene expression in the blood. This NIEHS-funded study could be a first step in developing accurate new tools to detect acetaminophen overdose in humans. Overdose of acetaminophen, the active ingredient in many over-the-counter pain relievers, is a leading cause of liver failure in the United States and is often difficult to diagnose. An estimated 50,000 people seek emergency room treatment for acetaminophen overdose each year.

The research published online Exit NIEHS in the Proceedings of the National Academy of Sciences shows that gene expression data from blood cells can provide valuable information about acetaminophen levels well before liver damage can be detected by other methods, including serum markers and liver biopsies.

"In time, this approach could give physicians a powerful new genomics tool to help patients who cannot estimate how much acetaminophen they consumed. Early detection of acetaminophen overdose can be helpful in preventing or treating resulting liver damage," said Richard S. Paules, Ph.D., principal investigator and director of the Microarray Core Facility at NIEHS and senior author on the new paper.

The researchers would like to build on their findings to develop a simple procedure that clinicians could use in the emergency room to estimate the level of acetaminophen exposure and the potential damage to the liver. This would be especially beneficial for patients such as the elderly, suicidal and semi-comatose who are unable to provide an accurate estimate.

To carry out their study, the researchers developed and then analyzed gene expression signatures, patterns of gene activity, in rats exposed to various doses of acetaminophen. Using microarrays, high-throughput assessment tools that allow scientists to see how differences in gene expression are linked to specific conditions, the researchers were able to determine which genes were turned on or turned off in response to different levels of acetaminophen. Once they selected the gene sets, they tested them for accuracy and found the signature gene lists were able to predict exposure to toxic versus nontoxic doses with very high accuracy (88.9-95.8 percent) - while the more traditional predictors, of clinical chemistry, hematology and pathology were approximately 65 to 80 percent accurate.

"Although it was not the main focus of our study, we wanted to see how applicable this gene expression profiling of blood cells was to humans," said Raymond W. Tennant, Ph.D., supervisory biologist in the NIEHS Laboratory of Molecular Toxicology, and a co-author on the study.

The NIEHS researchers compared the animal data with data from RNA in blood drawn from individuals who had been admitted to the University of North Carolina emergency room for acetaminophen overdose intoxication. When they compared the toxic blood samples to the samples from normal healthy volunteers, the researchers saw a striking difference.

"Although there are already some good tools available to emergency room physicians to detect liver injury, additional information concerning the level of exposures and/or the degree of liver injury could significantly help us in treating acetaminophen overdose patients," said Paul Watkins, M.D., director, General Clinical Research Center at the University of North Carolina, Chapel Hill and co-author on the paper.

Reference: Bushel PR, Heinloth AN, Li J, Huang L, Chou JW, Boorman GA, Malarkey DE, Houle CD, Ward SW, Wilson RE, Fannin RD, Russo MW, Watkins PB, Tennant RW, and Paules RS. Exit NIEHS 2007. Blood gene expression signatures predict exposure levels. Proc Natl Acad Sci U S A.DOI 10.1073 PNAS.0706987104 (2007).


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