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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
pharmacology, toxicology and pharmaceutics
Regulation of gene expression in brain tissues of rats repeatedly treated by the highly abused opioid agonist, oxycodone: Microarray profiling and gene mapping analysis
Drug Metabolism and Disposition, Volume 38, No. 1, Year 2010
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Description
Although oxycodone is the most often used opioid agonist, it remains one of the most understudied drugs. We used microarray analysis to better understand the global changes in gene expression in brain tissues of rats repeatedly treated with oxycodone. Many genes were significantly regulated by oxycodone (e.g., Fkbp5, Per2, Rt1.Dα, Slc16a1, and Abcg2). Validation of the microarray data by quantitative real-time-polymerase chain reaction (Q-PCR) indicated that there was a strong significant correlation (r = 0.979, p < 0.0000001) between the Q-PCR and the microarray data. Using MetaCore (a computational platform), many biological processes were identified [e.g., organic anion transport (p = 7.251 x 10-4) and regulation of immune response (p = 5.090 × 10-4)]. Among the regulated genes, Abcg2 mRNA was up-regulated by 2.1-fold, which was further confirmed by immunoblotting (1.8-fold up-regulation). Testing the Abcg2 affinity status of oxycodone using an Abcg2 ATPase assay suggests that oxycodone behaves as an Abcg2 substrate only at higher concentrations (≥ 500 μM). Furthermore, brain uptake studies demonstrated that oxycodone-induced Abcg2 up-regulation resulted in a significant (p < 0.05) decrease (∼2-fold) in brain/plasma ratios of mitoxantrone. These results highlight markers/mediators of neuronal responses and identify regulatory pathways involved in the pharmacological action of oxycodone. These results also identify genes that potentially modulate tolerance, dependence, immune response, and drug-drug interactions. Finally, our findings suggest that oxycodone-induced up-regulation of Abcg2 enhanced the efflux of the Abcg2 substrate, mitoxantrone, limiting its brain accumulation and resulting in an undesirable drug-drug interaction. Extrapolating these results to other Abcg2 substrates (e.g., dauno-rubicin and doxorubicin) indicates that the brain uptake of these agents may be affected if they are administered concomitantly with oxycodone. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.
Authors & Co-Authors
Hassan, Hazem Emad Eldin
United States, Baltimore
University of Maryland School of Pharmacy
Egypt, Helwan
Faculty of Pharmacy
Myers, Alan Lewis
United States, Baltimore
University of Maryland School of Pharmacy
United States, Des Moines
Drake University
Lee, Insong James
United States, Baltimore
University of Maryland School of Pharmacy
United States, Baltimore
Notre Dame of Maryland University
Chen, Hegang
United States, Baltimore
University of Maryland School of Medicine
Coop, Andrew
United States, Baltimore
University of Maryland School of Pharmacy
Eddington, Natalie D.
United States, Baltimore
University of Maryland School of Pharmacy
Statistics
Citations: 26
Authors: 6
Affiliations: 5
Identifiers
Doi:
10.1124/dmd.109.029199
ISSN:
00909556
e-ISSN:
1521009X
Research Areas
Genetics And Genomics
Study Approach
Quantitative