Breast cancer resistance protein: mediating the trans-placental transfer of glyburide across the human placenta.
Members of the ATP-binding cassette (ABC) efflux transporter family, including P-glycoprotein (PGP), the multidrug resistance-associated proteins (MRPs) and the breast cancer resistance protein (BCRP) have been shown to be highly expressed in the human placenta. Recent studies documented that the oral hypoglycemic glyburide does not cross the human placenta to an appreciable extent. Furthermore, the trans-placental transfer of glyburide has been shown not to be affected by either the presence of PGP inhibitor, verapamil or MRP inhibitor, indomethacin. Therefore, our objective was to identify other human placental ABC transporters potentially involved in limiting the trans-placental transfer of glyburide to the fetus. [(3)H]-glyburide transport was examined in brush border human placental vesicles in the presence or absence of specific inhibitors. Prepared vesicles were 70% oriented right-side-out and demonstrated 25-27 fold enrichment as compared to whole placenta. Functional studies demonstrated significant increases in the intra-vesicular accumulation of [(3)H]-glyburide in vesicles treated with the BCRP inhibitor, novobiocin. In contrast, PGP inhibition as well as MRP inhibition did not affect [(3)H]-glyburide accumulation. This is the first evidence to clearly indicate that glyburide is preferentially transported by BCRP, in the brush border of the human placenta. Our study also indicates that BCRP likely effluxes substrates in the fetal to maternal direction in the human placenta.
Gedeon
C
C
University of Toronto, Department of Pharmacology, Toronto, Ontario, Canada.
Anger
G
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Piquette-Miller
M
M
Koren
G
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D001692:Biological Transport; D005260:Female; D005905:Glyburide / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010920:Placenta / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005905:Glyburide; D007004:Hypoglycemic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D014700:Verapamil; C116614:ABCG2 protein, human