Regulation of gene expression in brain tissues of rats repeatedly treated by the highly abused opioid agonist, oxycodone: microarray profiling and gene mapping analysis.
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.Dalpha, 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 x 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 (> or = 500 microM). Furthermore, brain uptake studies demonstrated that oxycodone-induced Abcg2 up-regulation resulted in a significant (p < 0.05) decrease (approximately 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., daunorubicin and doxorubicin) indicates that the brain uptake of these agents may be affected if they are administered concomitantly with oxycodone.
Hassan
Hazem E
HE
Department of Pharmaceutical Sciences, School of Pharmacy, School of Medicine, University of Maryland, Baltimore, Maryland, USA.
Myers
Alan L
AL
Lee
Insong J
IJ
Chen
Hegang
H
Coop
Andrew
A
Eddington
Natalie D
ND
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D016000:Cluster Analysis; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004347:Drug Interactions / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D053263:Gene Regulatory Networks / Q000235:genetics*; D007700:Kinetics; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008942:Mitoxantrone / Q000097:blood / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010098:Oxycodone / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019966:Substance-Related Disorders / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C489249:Abcg2 protein, rat; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; D008942:Mitoxantrone; D010098:Oxycodone; D000251:Adenosine Triphosphatases