An integrated study of acute effects of valproic acid in the liver using metabonomics, proteomics, and transcriptomics platforms.
An integrated omics approach was undertaken in order to elucidate a systems biology level understanding of the acute hepatotoxcity of valproic acid (VPA). Metabonomics, proteomics and gene expression microarray platforms were employed in this systems biology study. CD-1 female pregnant mice were injected subcutaneously with 600 mg/kg VPA or vehicle control. Urine, serum, and liver tissue were collected at 6, 12, and 24 h after dosing. Principal component analysis (PCA) of the metabonomics data showed clustering of the dosed groups away from the controls for the urine samples. Looser clustering was seen in the other sample sets investigated. However, VPA administration resulted in altered glucose concentrations in urine samples at 12 and 24 h and in aqueous liver tissue extracts at 12 h after VPA administration. Proteomics studies identified two proteins, glycogen phosphorylase and amylo-1,6-glucosidase, which were increased in dosed animals relative to control. Both of these proteins are involved in converting glycogen to glucose. Examination of the expression of 20,000 liver genes did not reveal significantly altered expression at 6, 12, or 24 h after VPA exposure. The combined studies indicated a perturbation in the glycogenolysis pathway following administration of VPA.
Schnackenberg
Laura K
LK
Division of Systems Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, 72079, USA.
Jones
Richard C
RC
Thyparambil
Sheeno
S
Taylor
Jason T
JT
Han
Tao
T
Tong
Weida
W
Hansen
Deborah K
DK
Fuscoe
James C
JC
Edmondson
Ricky D
RD
Beger
Richard D
RD
Dragan
Yvonne P
YP
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010455:Peptides / Q000378:metabolism; D011247:Pregnancy; D040901:Proteomics; D014635:Valproic Acid / Q000378:metabolism / Q000494:pharmacology*
D000927:Anticonvulsants; D010455:Peptides; D014635:Valproic Acid; D005947:Glucose