ABC Transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) Expression in the Developing Human CNS

Abstract

P-glycoprotein (P-gp/ABCB1), multidrug resistance protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are plasma membrane efflux pumps that limit the intracellular uptake and retention of numerous lipophilic, amphipathic xeno-and endobiotics. Little is known about the neonatal and developmental expression of P-gp/ABCB1, MRP1/ABCC1, and BCRP/ ABCG2 in the human central nervous system (CNS), therefore postmortem CNS tissue from infants born 22 0/7 -42 0/7 week gestation and adults was immunostained to determine their ontogeny and cellular localization. P-gp/ABCB1 imunostaining was observed in microvessel endothelial cells as early as 22 0/7 weeks, increasing in prevalence and intensity with maturation, and later in gestation in large pyramidal neurons. MRP1/ABCC1 immunostaining was prominent early in the choroid plexus and ventricular ependyma, and noted later in large pyramidal neurons. BCRP/ABCG2 expression was limited to microvessel endothelial cells. P-gp/ABCB1, MRP1/ABCC1 and BCRP/ ABCG2 in adult brain matched term newborn CNS but with more intense immunostaining. We conclude that P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 are expressed in a developmental, cell specific, fashion in the human CNS. The complementary pattern of P-gp/ABCB1 and BCRP/ ABCG2 at the blood-brain with MRP1/ABCC1 at the blood-CSF barriers may limit CNS uptake and retention of drugs and toxins in neonates.

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

“…P-gp expression in the mouse brain was limited during late embryogenesis and the newborn period and increased remarkably with postnatal maturation reaching adult levels by day 21 of life (23). In humans, the intensity of P-gp immunostaining in the microvessel endothelial cell increased from GA 22 wk up to term but the P-gp intensity at term was still significantly lower when compared to adults (25).…”

“…Since Virgintino et al did not investigate the expression of P-gp in the developing human cortex at GA 20 wk, it is possible that P-gp may have already been expressed at the endothelial cells of the cortex microvessel before GA 22 wk. Similarly, the youngest human fetal brain in the study, GA 22 wk, was stained positive for P-gp (25).…”

“…However, even at term, P-gp expression in the fetus is low compared to adults (25). In contrast, the ontogeny of P-gp in the developing human infant has not been previously studied.…”

“…In humans, P-gp immunoreactivity was detected as early as 8-12 wk gestation in the fetal brain with its prevalence and intensity progressively increased with advancing age (25)(26)(27). However, even at term, P-gp expression in the fetus is low compared to adults (25).…”

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

“…In humans, ABCC1 (also known as MRP1) has been reported to be on the luminal side of brain capillary endothelial cells in samples taken after neurosurgical procedures 26 and in hippocampal neurons and astrocyte end-feet from patients with mesial temporal lobe epilepsy, 27 but not in brain microvessel endothelial cells or perivascular astrocytes isolated from humans without brain disease, 28 suggesting upregulation and/or relocation during stress. Undetectable or low level expression of ABCC1 associated with cerebral blood vessels in humans without brain disease, 28,29 and the above referenced reports of multiple CNS cell types expressing ABCC1 in humans with brain disease, are consistent with our immunohistochemical data (Fig.…”