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ToxSci Advance Access originally published online on September 22, 2006
Toxicological Sciences 2006 94(2):379-387; doi:10.1093/toxsci/kfl116
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Identification of Genes Controlled by the Pregnane X Receptor by Microarray Analysis of mRNAs from Pregnenolone 16{alpha}-Carbonitrile–Treated Rats

Jeffrey Guzelian*, Joyce L. Barwick{dagger}, Lawrence Hunter{ddagger}, Tzu L. Phang{ddagger}, Linda C. Quattrochi{dagger},1 and Philip S. Guzelian{dagger}

* Department of Medicine, University of Colorado, Boulder, Colorado 80262 {dagger} Section of Medical Toxicology, School of Medicine, Denver, Colorado 80262 {ddagger} Center for Computational Pharmacology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262

Received May 31, 2006; accepted August 2, 2006

Mammalian liver contains a pregnane X receptor (PXR, NR1I2), which binds drugs and other xenobiotics, and stimulates (or suppresses) expression of numerous genes involved in the metabolic elimination of foreign compounds and some toxic endogenous substances. In the present study, we used microarray analysis to identify genes whose expression in rat liver was significantly altered by pregnenolone 16{alpha}-carbonitrile (PCN) treatment. PCN is a synthetic steroid that induces cytochrome P4503A expression and is hepatoprotective by increasing resistance to subsequent stressful insults. Significant induction was seen for 138 genes while expression of 82 genes was significantly repressed. We found induction of genes known to be induced by PCN, such as enzymes involved in drug metabolism and transport. In addition, many genes were differentially expressed whose functions concerned intracellular metabolism, transport of essential small molecules, cell cycle, and redox balance. Our results support the idea that the domain of PXR-controlled gene networks may be even more extensive than currently thought and may extend to functions apart from xenobiotic metabolism.

Key Words: pregnenolone 16{alpha}-carbonitrile; pregnane X receptor; microarray; gene expression profiling.


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