BCRP at the blood-brain barrier: genomic regulation by 17β-estradiol.

At the blood-brain barrier (BBB), the ABC transporter breast cancer resistance protein (BCRP) actively extrudes a variety of therapeutic drugs, including cytostatics, and diminishes their pharmacological efficacy in the brain. Consequently, new strategies to circumvent BCRP-mediated multidrug resistance in the CNS are required. One major approach to increase brain drug levels is to manipulate signaling mechanisms that control transporter expression and function. In the present study, we investigated the long-term effect of 17β-estradiol on BCRP in an ex vivo model of isolated rat brain capillaries. BCRP function and protein expression were decreased after 6 h of incubation with nanomolar concentrations of 17β-estradiol in capillaries from male and female rats. Concomitantly, levels of BCRP mRNA were also reduced by 17β-estradiol suggesting that the transporter is down-regulated via a genomic pathway. Additionally, we identified the presence of both estrogen receptor (ER) subtypes α and β at the rat BBB. Experiments using selective ER agonists and antagonists revealed that ER subtype β is responsible for the hormone-induced reduction of BCRP function and protein expression. These findings were confirmed by the use of ERKO mice. Blocking the proteasome-dependent degradation by lactacystin reversed the 17β-estradiol-mediated decrease of BCRP supposing that transcriptional down-regulation of the efflux transporter is paralleled by protein degradation. This study demonstrates that 17β-estradiol induces the down-regulation of BCRP on transcriptional and translational levels via the activation of ERβ in rat brain capillaries after 6 h. These results could help to improve brain targeting of BCRP substrates in the treatment of CNS diseases such as brain tumors and also contribute to an enlarged understanding of BCRP-drug interactions at a chronic intake of phytoestrogens and oral contraceptives.