Proteomics to display lovastatin-induced protein and pathway regulation in rat liver.
Lovastatin is a lipid lowering agent that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory enzyme in cholesterol biosynthesis. In this study the pattern of gene network regulation induced in hepatic proteins as a response to lovastatin treatment was analyzed by proteomics. In livers of male F344 rats treated with 1.6 mg/kg/day lovastatin or 150 mg/kg/day lovastatin for seven days, 36 proteins were found to be significantly altered (p<0.001) in relation to treatment. The changed proteins were classified according to their cellular function and participation in biochemical pathways. The following observations were made: (i) inhibition of HMG-CoA reductase provoked a regulatory response in the cholesterol synthesis pathway including the induction of cytosolic HMG-CoA synthase and of isopentenyl-diphosphate delta-isomerase, (ii) manipulation of the lipid metabolism triggered alterations in key enzymes of the carbohydrate metabolism, and (iii) lovastatin treatment was associated with signs of toxicity as reflected by changes in a heterogeneous set of cellular stress proteins involved in functions such as cytoskeletal structure, calcium homeostasis, protease inhibition, cell signaling or apoptosis. These results present new insights into liver gene network regulations induced by lovastatin and illustrate a yet unexplored application of proteomics to discover new targets by analysis of existing drugs and the pathways that they regulate.
Steiner
S
S
Large Scale Proteomics Corporation, Rockville, MD 20850, USA. sandra.steiner@lsbc.com
Gatlin
C L
CL
Lennon
J J
JJ
McGrath
A M
AM
Aponte
A M
AM
Makusky
A J
AJ
Rohrs
M C
MC
Anderson
N L
NL
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001711:Biotransformation; D002118:Calcium / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002784:Cholesterol / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D009711:Nucleotides / Q000378:metabolism; D018384:Oxidative Stress; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020543:Proteome; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction
D000596:Amino Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009711:Nucleotides; D011506:Proteins; D020543:Proteome; D002784:Cholesterol; D008148:Lovastatin; D002118:Calcium