Pregnane X Receptor (PXR) Regulates P-Glycoprotein at the Blood-Brain Barrier: Functional Similarities between Pig and Human PXR

• Published in: The Journal of pharmacology and experimental therapeutics 2009-04, Vol.329 (1), p.141-149
• Main Authors: Ott, Melanie, Fricker, Gert, Bauer, Björn
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Blood-Brain Barrier - physiology; Blotting, Western; Bridged Bicyclo Compounds - pharmacology; Cell Separation; Cells, Cultured; Endothelial Cells - drug effects; Fluoresceins - metabolism; Humans; Immunohistochemistry; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Phloroglucinol - analogs & derivatives; Phloroglucinol - pharmacology; Receptors, Steroid - drug effects; Receptors, Steroid - genetics; Receptors, Steroid - physiology; Reverse Transcriptase Polymerase Chain Reaction; Rifampin - pharmacology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Swine; Terpenes - pharmacology; Up-Regulation - drug effects; Xenobiotics - pharmacology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.149690

Pharmacotherapy of central nervous system (CNS) disorders is impaired by the drug efflux transporter, P-glycoprotein, which limits drug penetration across the blood-brain barrier into the CNS. One strategy to increase brain drug levels is to modulate P-glycoprotein regulation. This approach requires understanding of the mechanisms that control transporter expression and function. One mechanism through which P-glycoprotein is regulated is the nuclear receptor, pregnane X receptor (PXR). Xenobiotics including drugs activate PXR and induce P-glycoprotein, which potentially affects pharmacokinetics/pharmacodynamics of coadministered drugs. Because rodent models are not suitable to predict xenobiotic interactions with human PXR, in a porcine model, we studied functional similarities between pig and human PXR. We used brain capillary endothelial cells from pig to study the effect of PXR activation on P-glycoprotein. To activate PXR, we used the PXR ligands, rifampicin, hyperforin, and pregnenolone-16α-carbonitrile (PCN), and measured abcb1 mRNA with quantitative polymerase chain reaction, P-glycoprotein expression with Western blotting, and P-glycoprotein transport activity with a calcein assay. We provide first proof of principle that the human PXR ligands, rifampicin and hyperforin, but not the rodent PXR ligand, PCN, activate pig PXR at the blood-brain barrier and induce mRNA, protein expression, and transport activity of P-glycoprotein. Our data indicate functional similarities between human and pig PXR that suggest the pig model could be useful for predicting xenobiotic-PXR interactions in humans. Because PXR is crucial in controlling drug efflux transporters, our findings will contribute to a better understanding of the regulation of blood-brain barrier function, which could potentially have important clinical implications for the treatment of CNS disorders.