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.

• 17α-Ethinylestradiol
• bisphenol A
• blood–brain barrier
• breast cancer resistance protein
• xenoestrogen

Acknowledgements

The authors would like to thank Prof. Gert Fricker for support and Patrick Schirm, Adrían Cortez and Paranchai Boonsawat for experimental help.