Hepatic Gene Expression Response to Acute Indomethacin Exposure
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ORIGINAL RESEARCH ARTICLE
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Hepatic Gene Expression Response to Acute Indomethacin Exposure William A. LaFramboise,1,2 Kelly L. Bombach,2 Andrew R. Pogozelski,2 Ryan F. Cullen,2 Noah Muha,3 James Lyons-Weiler,1 Scott J. Spear,1 Rajiv J. Dhir,1 Robert D. Guthrie4 and James A. Magovern1 1
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
2
Department of Cardiothoracic Surgery, Drexel University School of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
3
Zivic Laboratories, Zelienople, Pennsylvania, USA
4
Department of Pediatrics, Drexel University School of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
Abstract
Background: Rising morbidity and mortality related to the use of NSAIDs has led to the withdrawal of some of these agents and reconsideration of the adverse effects and usage paradigms of commonly available NSAIDs. Our objective in this study was to assay molecular indicators of acute hepatic injury associated with the administration of indomethacin, a prototypical NSAID, metabolized by the liver that undergoes enterohepatic circulation with associated gastrointestinal adverse effects. Methods: Analysis of gene expression, using high-throughput, ADME (absorption, distribution, metabolism, excretion)-specific microarrays, was performed on RNA extracted from the livers of control or indomethacin treated rats, in parallel with serum enzyme tests and histological analysis of paraffin-embedded liver specimens. Male Sprague-Dawley rats (n = 45) were administered intraperitoneal injections of indomethacin for 3 days at the recommended normal dose (6.7 mg/kg), indomethacin at a high dose (20 mg/kg) or vehicle alone (controls). Results: Upon termination of the study on day 4, serum γ-glutamyl transferase activity and alkaline phosphatase/ alanine aminotransferase ratios were significantly elevated in both high- and normal-dose cohorts compared with vehicle-treated animals. Diffuse microvascular steatosis was present in hepatic serial sections obtained from all animals subjected to the high-dosage regimen. High-resolution microarray analysis (six replicates/gene/animal) identified 256 genes, after outlier removal, in 17 functional classifications that were significantly altered by the high, but not by the normal dosage. These included depression of 10 of 11 cytochrome P450 genes (2B3, 2C70, 1A2-P2, 4F1, 2E1, 3A1, 2F1, 3AP7, 2C11, phenobarb-inducible P6) and 7 of 9 genes involved in the response to reactive oxygen species (e.g. glutathione reductase, glutathione transferase, and superoxide dismutase). Of 16 genes associated with toxin removal, nine exhibited significantly decreased transcripts. There was a marked shift away from lipid metabolism (decreased expression of eight genes) towards glucose utilization associated with steatosis. Despite the compromise of detoxification programs and a shift in metabolic substrate utilization, a compensatory remodeling response was activated, inclu
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