title: Pregnane X receptor (PXR) regulates P-glycoprotein at the blood-brain barrier: functional similarities between pig and human PXR.
abstract: 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-16alpha-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.
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ott
authors.forename: Gert
authors.initials: G
authors.lastname: Fricker
authors.forename: Björn
authors.initials: B
authors.lastname: Bauer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D015153:Blotting, Western; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002469:Cell Separation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011987:Receptors, Steroid / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D013552:Swine; D013729:Terpenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001643:Bridged Bicyclo Compounds; D005452:Fluoresceins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013729:Terpenes; D015262:Xenobiotics; D010696:Phloroglucinol; C001654:hyperforin; C007740:fluorexon; D012293:Rifampin