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Article

Systems Toxicology: Integrated Genomic, Proteomic and Metabonomic Analysis of Methapyrilene Induced Hepatotoxicity in the Rat

Supporting Info

Andrew Craig,^† James Sidaway,^‡ Elaine Holmes,^† Terry Orton,^‡ David Jackson,^§ Rachel Rowlinson,^§ Janice Nickson,^§ Robert Tonge,^§ Ian Wilson, and Jeremy Nicholson*^†

Biological Chemistry, Biomedical Sciences Division, Faculty of Life Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, United Kingdom, Safety Assessment, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK104 TG, United Kingdom, Pathways, Discovery Enabling Capabilities and Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom, and Department of Drug Metabolism and Pharmacokinetics, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK104TG, United Kingdom

J. Proteome Res., 2006, 5 (7), pp 1586–1601

DOI: 10.1021/pr0503376

Publication Date (Web): June 15, 2006

†

Imperial College London.

‡

Safety assessment, AstraZeneca.

Discovery Enabling Capabilities and Sciences, AstraZeneca.

Department of Drug Metabolism and Pharmacokinetics, AstraZeneca.

To whom correspondence should be addressed. E-mail: j.nicholson@ imperial.ac.uk.

Abstract

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.

Keywords: genomics • microarray • proteomics • metabonomics • hepatotoxicity • methapyrilene

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