Proteomic characterization of the effects of clofibrate on protein expression in rat liver.
Clofibrate is a peroxisome proliferator known to induce liver tumours in rats. A proteomics study was conducted to provide new insights into the molecular mechanisms of clofibrate-induced non-genotoxic hepatocarcinogenesis. Rats were treated with 250 mg/kg day clofibrate orally and sacrificed after 7 days. Proteins extracted from the liver were analysed by 2-DE using DIGE technology. The protein identification performed by MS showed that clofibrate induced up-regulation of 77 proteins and down-regulation of 27 proteins. The highest expression ratios corresponded to proteins involved in a series of biochemical pathways such as lipid metabolism, fatty acid metabolism, amino acid metabolism, protein metabolism, citric acid cycle, xenobiotic detoxification and oxidative stress. Proteins implicated in cell proliferation and apoptosis, such as prohibitin, 10-formyl tetrahydrofolate dehydrogenase, senescence marker protein-30, pyridoxine 5'-phosphate oxidase and vimentin, were also identified as being regulated. These results provide leads for further investigations into the molecular mechanisms of liver tumours induced by clofibrate. In addition, MS results showed that a series of regulated proteins were detected as several spots corresponding to different pI and/or M(r). Differential effects on those variants could result from specific PTM and could be a specific molecular signature of the clofibrate-induced protein expression modulation in rat liver.
Drug Safety Evaluation, Sanofi Aventis, Vitry-sur-Seine, France. jean-francois.leonard@sanofi-aventis.com
Jean-François
JF
Léonard
Martine
M
Courcol
Claire
C
Mariet
Aurore
A
Charbonnier
Eric
E
Boitier
Marc
M
Duchesne
Fabienne
F
Parker
Bruno
B
Genet
Françoise
F
Supatto
Ruth
R
Roberts
Jean-Charles
JC
Gautier
D000595:Amino Acid Sequence; D000818:Animals; D002853:Chromatography, Liquid; D002994:Clofibrate / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D015971:Gene Expression Regulation, Enzymologic; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008110:Liver Extracts / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D011506:Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014357:Trypsin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D008110:Liver Extracts; D011506:Proteins; D014357:Trypsin; D002994:Clofibrate