ToxSci Advance Access published online on June 2, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl030
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1 Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
* To whom correspondence should be addressed. Toxicogenomics provides the ability to examine in greater detail the underlying molecular events that precede and accompany toxicity, thus allowing prediction of adverse events at much earlier times compared to classical toxicological endpoints. Acetaminophen (APAP) is a pharmaceutical that has similar metabolic and toxic responses in rodents and humans. Recent gene expression profiling studies with APAP found an oxidative stress signature at a sub-toxic dose that we hypothesized can be phenotypically anchored to conventional biomarkers of oxidative stress. Liver tissue was obtained from experimental animals used to generate microarray data where male rats were given APAP at sub-toxic (150 mg/kg), or overtly toxic (1500 and 2000 mg/kg) doses and sacrificed at 6, 24, or 48 hrs. Oxidative stress in liver was evaluated by a diverse panel of markers that included assessing expression of base excision repair (BER) genes, quantifying oxidative lesions in genomic DNA, and evaluating protein and lipid oxidation. A sub-toxic dose of APAP produced significant accumulation of nitrotyrosine protein adducts, while both sub-toxic and toxic doses caused a significant increase in 8-hydroxy-deoxyguanosine. Only toxic doses of APAP significantly induced expression levels of BER genes. None of the doses examined resulted in a significant increase in the number of abasic sites, or in the amount of lipid peroxidation. The accumulation of nitrotyrosine and 8-hydroxy-deoxyguanosine adducts phenotypically anchors the oxidative stress gene expression signature observed with a sub-toxic dose of APAP, lending support to the validity of gene expression studies as a sensitive and biologically-meaningful endpoint in toxicology.
Received February 1, 2006
Accepted May 25, 2006
Systems Toxicology
Phenotypic Anchoring of Acetaminophen-Induced Oxidative Stress with Gene Expression Profiles in Rat Liver
Christine L. Powell 1,
Oksana Kosyk 2,
Pamela K. Ross 2,
Robert Schoonhoven 2,
Gunnar Boysen 2,
James A. Swenberg 1,
Alexandra N. Heinloth 3,
Gary A. Boorman 4,
Michael L. Cunningham 5,
Richard S. Paules 3,
and
Ivan Rusyn 1 *
2 Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
3 National Center for Toxicogenomics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
4 Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
5 Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
Ivan Rusyn, E-mail: iir{at}unc.edu
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