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
Affiliations
Hafsah Mughis
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
Phetcharawan Lye
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
Guinever E. Imperio
Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada
Enrrico Bloise
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Departmento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
Stephen G. Matthews
Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Sinai Health System, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada; Department of Obstetrics & Gynaecology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Corresponding author. Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Medical Sciences Building Room 3207, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
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.
