The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the
free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the
relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a
variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein
(P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are
regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC-
β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However,
it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain
microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the
transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back
into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug
delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and
cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an
important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This
article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.