ToxSci Advance Access originally published online on June 2, 2006
Toxicological Sciences 2006 93(1):213-222; doi:10.1093/toxsci/kfl030
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Phenotypic Anchoring of Acetaminophen-Induced Oxidative Stress with Gene Expression Profiles in Rat Liver
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* Curriculum in Toxicology and Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and National Center for Toxicogenomics, Environmental Toxicology Program, and ¶ Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Received February 1, 2006; accepted May 25, 2006
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 end points. 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 subtoxic 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 subtoxic (150 mg/kg) or overtly toxic (1500 and 2000 mg/kg) doses and sacrificed at 6, 24, or 48 h. 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 subtoxic dose of APAP produced significant accumulation of nitrotyrosine protein adducts. Both subtoxic and toxic doses caused a significant increase in 8-hydroxy-deoxyguanosine (8-OH-dG) as well as a significant decrease in glutathione (GSH) content. 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-OH-dG adducts along with reduced GSH content in the liver phenotypically anchors the oxidative stress gene expression signature observed with a subtoxic dose of APAP, lending support to the validity of gene expression studies as a sensitive and biologically meaningful end point in toxicology.
Key Words: toxicogenomics; acetaminophen; nitrotyrosine; 8-hydroxy-deoxyguanosine; oxidative stress; lipid peroxidation.
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