NDLI: The characterization of PPARα ligand drug action in an in vivo model by comprehensive differential gene expression profiling

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Functional & Integrative Genomics : Volume 1, Issue 4, March 2001

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Functional & Integrative Genomics : Volume 1, Issue 1, May 2000

The characterization of PPARα ligand drug action in an in vivo model by comprehensive differential gene expression profiling

Content Provider	Springer Nature Link
Author	Gould Rothberg, Bonnie E. Sundseth, Scott S. DiPippo, Vincent A. Brown, Peter J. Winegar, Deborah A. Gottshalk, William K. Shey, Suresh G. Rothberg, Jonathan M.
Copyright Year	2000
Abstract	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 (PPARα) 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 PPARα 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.
Starting Page	294
Ending Page	304
Page Count	11
File Format	PDF
ISSN	1438793X
Journal	Functional & Integrative Genomics
Volume Number	1
Issue Number	5
Language	English
Publisher	Springer-Verlag
Publisher Date	2000-10-11
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Content Type	Text
Resource Type	Article
Subject	Genetics Medicine

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