Hypoxia modulates P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) drug transporters in Brain Endothelial Cells of the Developing Human Blood-Brain Barrier

Abstract

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two multidrug resistance (MDR) transporters expressed at the blood-brain barrier (BBB). They confer protection against entry of harmful molecules into the fetal brain. The fetus develops under relatively low oxygen concentrations; however, pregnancy disorders (including pre-eclampsia) may lead to even lower intrauterine oxygen levels. We investigated the effects of hypoxia on transporter expression and activity in human fetal brain endothelial cells (hfBECs) isolated in early and mid-gestation. Results indicate decreased BCRP protein and activity under hypoxia in early-gestation hfBECs. Mid-gestation hfBECs exhibited an increase in P-gp and BCRP activity following hypoxia. Results suggest a hypoxia-induced reduction in fetal brain protection in early-pregnancy, but a potential increase in transporter-mediated protection at the BBB during mid-gestation. This would modify accumulation of various key P-gp and BCRP physiological and pharmacological substrates in the developing fetal brain and may play a role in the pathogenesis of neurodevelopmental disorders commonly associated with in utero hypoxia.