title: The xenoestrogens ethinylestradiol and bisphenol A regulate BCRP at the blood-brain barrier of rats.
abstract: 1. Breast cancer resistance protein (BCRP) is an ABC-transporter at the blood-brain barrier (BBB) facilitating efflux of xenobiotics into blood. Expression and function are regulated via estrogen-receptors (ERs). 2. 17α-Ethinylestradiol (EE2) and bisphenol A (BPA) represent two prominent xenoestrogens. We studied whether EE2 and BPA regulate BCRP function and expression upon a 6 h treatment in an ER-dependent manner in a rat BBB-ex-vivo-model. 3. Isolated brain capillaries were incubated with EE2 or BPA. BCRP function and expression were analyzed by confocal microscopy and Western-Blot. ERα-antagonist MPP and ER-antagonist ICI182.780 were used to study involvement of ERs. 4. EE2 and BPA down-regulated BCRP transport function and expression. EE2 effects occurred at pharmacologically relevant doses, BPA exhibited only weak influences. Down-regulation by EE2 was reversed by ICI but not MPP. BPA effects were not reversed by either antagonist. 5. EE2 is a potent regulator of BCRP expression and function acting by ERβ-stimulation. Oral contraception could alter uptake of pharmaceuticals to the brain and might thus be considered as an origin of central nervous system (CNS) side-effects. EE2 could also present a novel co-treatment to improve CNS-pharmacotherapy. BPA is a weak modulator of BCRP expression. Its effects appear not to be caused by ERs.
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg , Heidelberg , Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Nickel
authors.forename: Anne
authors.initials: A
authors.lastname: Mahringer
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000098826:Bisphenol A Compounds
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001559:Benzhydryl Compounds; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004997:Ethinyl Estradiol; D010636:Phenols; C489249:Abcg2 protein, rat; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: 17α-Ethinylestradiol; bisphenol A; blood–brain barrier; breast cancer resistance protein; xenoestrogen