Systems toxicology: integrated genomic, proteomic and metabonomic analysis of methapyrilene induced hepatotoxicity in the rat.
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.
Craig
Andrew
A
Biological Chemistry, Biomedical Sciences Division, Faculty of Life Sciences, Imperial College London, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, United Kingdom.
Sidaway
James
J
Holmes
Elaine
E
Orton
Terry
T
Jackson
David
D
Rowlinson
Rachel
R
Nickson
Janice
J
Tonge
Robert
R
Wilson
Ian
I
Nicholson
Jeremy
J
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D050356:Lipid Metabolism; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008701:Methapyrilene / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D009336:Necrosis / Q000139:chemically induced; D018384:Oxidative Stress / Q000187:drug effects; D011506:Proteins / Q000032:analysis; D040901:Proteomics; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
D006634:Histamine H1 Antagonists; D011506:Proteins; D008701:Methapyrilene