The characterization of PPAR alpha ligand drug action in an in vivo model by comprehensive differential gene expression profiling.
Expression pharmacogenomics includes differential gene expression (DGE) profiling of drug responses in model systems to generate a set of differentially modulated drug-responsive genes which can serve as a surrogate measure for drug action. In this manner, expression pharmacogenomics bridges the fields of genomics and medicinal chemistry. Additionally, modulated genes can be organized into metabolic and signaling pathways that highlight the mechanism of drug activity in a selected tissue. Here, we describe the application of expression pharmacogenomics to characterize a drug response in the clinically relevant in vivo model, the Sprague-Dawley rat. Following oral dosing of rats with GW9578, a novel synthetic peroxisome proliferator activated receptor alpha (PPAR alpha) ligand indicated for lipid disorders, we applied GeneCalling, a differential mRNA transcript profiling technique, to rat liver cDNA. Following GW9578 treatment, 2.4% of the rat liver genes were differentially expressed. We confirmed the sequence identity of 50 distinctly modulated genes. DGE was observed among genes representative of at least six discrete metabolic pathways. Furthermore, we observed up-regulation of 20 genes involved in mitochondrial, peroxisomal and microsomal fatty acid oxidation, consistent with molecular biological and clinical data indicating PPAR alpha ligand principal efficacy to be through increasing fatty acid metabolism. Those pathways regulated in our study that are potentially contributory to target effect, non-target adverse effects, or of unknown consequence include xenobiotic detoxification and steroid modification. Finally, comprehensive drug response profiling can lead to the serendipitous discovery of novel disease indications. In this case, these results suggest a potential novel indication for GW9578 in the treatment of X-linked adrenoleukodystrophy. We have shown, therefore, that the organization of DGE results into metabolic and signaling pathways can elucidate mechanisms of pharmacologically desired (i.e., efficacious) and, where appropriate, undesired (i.e., potentially deleterious) effects.
Gould Rothberg
B E
BE
CuraGen Corporation, 555 Long Wharf Drive, New Haven, CT 06511, USA. bgould@curagen.com
Sundseth
S S
SS
DiPippo
V A
VA
Brown
P J
PJ
Winegar
D A
DA
Gottshalk
W K
WK
Shenoy
S G
SG
Rothberg
J M
JM
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D002087:Butyrates; D000960:Hypolipidemic Agents; D008024:Ligands; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C121804:GW 9578