Organic anion transporting polypeptide 2B1 and breast cancer resistance protein interact in the transepithelial transport of steroid sulfates in human placenta.
The human placenta has both protective and nurturing functions for the fetal organism. Uptake and elimination of xenobiotics and endogenous substances are facilitated by various transport proteins from the solute carrier (SLC) and ABC families, respectively. A functional interaction of uptake and elimination, which is a prerequisite for vectorial transport across cellular barriers, has not been described for placenta. In this study, we examined expression of organic anion transporter (OAT) 4 (SLC22A11), organic anion transporting polypeptide (OATP) 2B1 (SLCO2B1, OATP-B), and breast cancer resistance protein (BCRP) (ABCG2) in human placenta (n = 71) because all three proteins are involved in transmembranal transfer of estrone 3 sulfate (E3S; metabolic product) and dehydroepiandrosterone sulfate (DHEAS; precursor molecule). On the mRNA level, we found a significant correlation of OATP2B1 and BCRP (R(2) = 0.534; p < 0.01) but not between OAT4 and BCRP (R(2) = -0.104; p > 0.05). Localization studies confirmed basal expression of OATP2B1 and apical expression of BCRP. To study functional interactions between OATP2B1 and BCRP, we developed a Madin-Darby canine kidney cell model expressing both transport proteins simultaneously (OATP2B1 and BCRP in the basal and apical membrane, respectively). Using this cell model in a transwell system resulted in a significantly increased basal to apical transport of both E3S and DHEAS, when both transporters were expressed with no change of transfer in the apical to basal direction. Taken together, these data show the potential for a functional interaction of OATP2B1 and BCRP in transepithelial transport of steroid sulfates in human placenta.
Grube
Markus
M
Department of Pharmacology, Friedrich Loefflerstrasse 23d, 17487 Greifswald, Germany. kroemer@uni-greifswald.de
Reuther
Sebastian
S
Meyer Zu Schwabedissen
Henriette
H
Köck
Kathleen
K
Draber
Katrin
K
Ritter
Christoph A
CA
Fusch
Christoph
C
Jedlitschky
Gabriele
G
Kroemer
Heyo K
HK
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D004285:Dogs; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C427207:SLC22A11 protein, human; C450859:SLCO2B1 protein, human; C025483:estradiol-17 beta-glucuronide; D004970:Estrone; D004958:Estradiol; D019314:Dehydroepiandrosterone Sulfate; C017296:estrone sulfate