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

Hafsah Mughis; Phetcharawan Lye; Guinever E Imperio; Enrrico Bloise; Stephen G Matthews

doi:10.1016/j.heliyon.2024.e30207

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

Heliyon. 2024 Apr 30;10(9):e30207. doi: 10.1016/j.heliyon.2024.e30207. eCollection 2024 May 15.

Authors

Hafsah Mughis^{1

2}, Phetcharawan Lye^{1

2}, Guinever E Imperio², Enrrico Bloise^{1

3}, Stephen G Matthews^{1

2

4

5}

Affiliations

¹ Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
² Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada.
³ Departmento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
⁴ Department of Obstetrics & Gynaecology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.
⁵ Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Abstract

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) multidrug resistance (MDR) transporters are localized at the luminal surface of the blood-brain barrier (BBB). They confer fetal brain protection against harmful compounds that may be circulating in the peripheral blood. The fetus develops in low oxygen levels; however, some obstetric pathologies such as pre-eclampsia, placenta accreta/previa may result in even greater fetal hypoxic states. We investigated how hypoxia impacts MDR transporters in human fetal brain endothelial cells (hfBECs) derived from early and mid-stages of pregnancy. Hypoxia decreased BCRP protein and activity in hfBECs derived in early pregnancy. In contrast, in hfBECs derived in mid-pregnancy there was 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 physiological and pharmacological substrates of P-gp and BCRP in the developing fetal brain and potentially contribute to the pathogenesis of neurodevelopmental disorders commonly associated with in utero hypoxia.

Keywords: Blood-brain barrier (BBB); Brain development; Breast cancer resistance protein (BCRP/ABCG2); Hypoxia; Multidrug resistance (MDR) transporters; Oxygen; P-glycoprotein (P-gp/ABCB1).