Integrated application of transcriptomics and metabonomics yields new insight into the toxicity due to paracetamol in the mouse.
Gene chip array (Affymetrix) data from liver tissue and high resolution 1H NMR spectra from intact liver tissue, tissue extracts and plasma have been analyzed to identify biochemical changes arising from hepatotoxicity in mice dosed with acetaminophen. These data sets have been co-interpreted in terms of common metabolic pathways. The principal metabolic changes comprised a decrease in hepatic glucose and glycogen in intact tissue, coupled with an increase in lipid content, with increases in the levels of glucose, pyruvate, acetate and lactate in plasma, and increases in alanine and lactate in the aqueous tissue extracts. Collectively these data provide evidence for an increased rate of hepatic glycolysis. The metabolic observations were consistent with the altered levels of gene expression relating to lipid and energy metabolism in liver which both preceded and were concurrent with the metabolic perturbations. The results show that these two technology platforms together offer a complementary view into cellular responses to toxic processes, providing new insight into the toxic consequences, even for well-studied therapeutic agents such as acetaminophen.
Coen
Muireann
M
Biological Chemistry, Biomedical Sciences Division, Faculty of Medicine, Imperial College, Sir Alexander Fleming Building, South Kensington, London SW7 2AZ, UK.
Ruepp
Stefan U
SU
Lindon
John C
JC
Nicholson
Jeremy K
JK
Pognan
François
F
Lenz
Eva M
EM
Wilson
Ian D
ID
D000082:Acetaminophen / Q000097:blood / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D007274:Injections, Intraperitoneal; D050356:Lipid Metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
D018712:Analgesics, Non-Narcotic; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase