Systems Toxicology: Integrated Genomic, Proteomic and Metabonomic Analysis of Methapyrilene Induced Hepatotoxicity in the Rat
| Autor: | Rachel Rowlinson, Andrew Craig, Robert Tonge, David A. Jackson, Ian D. Wilson, James E. Sidaway, Janice Nickson, Jeremy K. Nicholson, Terry C. Orton, Elaine Holmes |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Proteomics Microarray Methapyrilene Pharmacology Biology medicine.disease_cause Biochemistry Necrosis chemistry.chemical_compound medicine Animals Rats Wistar Dose-Response Relationship Drug Liver Diseases Antagonist Proteins Genomics General Chemistry Lipid Metabolism Rats Oxidative Stress Gene Expression Regulation Liver chemistry Toxicity Histamine H1 Antagonists Chemical and Drug Induced Liver Injury Signal transduction Histamine Oxidative stress Signal Transduction medicine.drug |
| Zdroj: | Journal of Proteome Research. 5:1586-1601 |
| ISSN: | 1535-3907 1535-3893 |
| DOI: | 10.1021/pr0503376 |
| Popis: | Administration of high doses of the histamine antagonist methapyrilene to rats causes periportal liver necrosis. The mechanism of toxicity is ill-defined and here we have utilized an integrated systems approach to understanding the toxic mechanisms by combining proteomics, metabonomics by 1H NMR spectroscopy and genomics by microarray gene expression profiling. Male rats were dosed with methapyrilene for 3 days at 150 mg/kg/day, which was sufficient to induce liver necrosis, or a subtoxic dose of 50 mg/kg/day. Urine was collected over 24 h each day, while blood and liver tissues were obtained at 2 h after the final dose. The resulting data further define the changes that occur in signal transduction and metabolic pathways during methapyrilene hepatotoxicity, revealing modification of expression levels of genes and proteins associated with oxidative stress and a change in energy usage that is reflected in both gene/protein expression patterns and metabolites. The difficulties of combining and interpreting multiomic data are considered. |
| Databáze: | OpenAIRE |
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