Developmental expression of multidrug resistance phosphoglycoprotein (P-gp) in the mouse fetal brain and glucocorticoid regulation.
The multidrug resistance gene (Abcb1) protein product, phosphoglycoprotein (P-gp) is expressed on the luminal surface of capillary endothelial cells of the adult blood-brain barrier (bbb). P-gp is critical for neuroprotection as it actively pumps substrates back into the capillary lumen. The fetal brain represents a primary target for many P-gp substrates; however, the developmental expression, function and regulation of Abcb1 in the fetal brain are not well understood. Approximately 10% of pregnant women undergo synthetic glucocorticoid therapy for the management of preterm labor (PTL), though the effects of synthetic glucocorticoid on P-gp in the fetal brain are not known. We hypothesize that in the fetal brain: 1) expression and function of Abcb1 will increase with advancing gestation; 2) synthetic glucocorticoids will up-regulate the expression of Abcb1 and 3) this increased expression will correspond to a decrease in brain accumulation of P-gp substrates. Pregnant FVB dams were euthanized on embryonic day (E) 15.5 or E18.5 and fetal brains were collected and analyzed for [(3)H]digoxin accumulation or P-gp expression. In another group, pregnant FVB dams were injected daily with either dexamethasone (DEX; 0.1mg/kg or 1mg/kg) or vehicle from E9.5-E15.5 (mid-gestation) or E12.5-E18.5 (late-gestation) and analyzed on E15.5 or E18.5. Abcb1a mRNA (P<0.01) and P-gp protein increased near term, corresponding to decreased [(3)H]digoxin accumulation in the fetal brain (P<0.001). DEX treatment during mid-gestation modified Abcb1 mRNA expression and P-gp function in a dose-, gestational age-, and sex-specific manner. In conclusion, P-gp mediated protection of the fetal brain increases with advancing gestation in an isoform-specific manner. Synthetic glucocorticoid exposure can modify expression and function of multidrug-resistance in the fetal brain, and this will likely have clinical implication given the extensive use of synthetic glucocorticoid in the management of PTL.
Petropoulos
Sophie
S
Department of Physiology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada.
Gibb
William
W
Matthews
Stephen G
SG
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D005938:Glucocorticoids; D012333:RNA, Messenger; D003907:Dexamethasone; C507084:Abcb1b protein, mouse