Nitrofurantoin transport by placental choriocarcinoma JAr cells: involvement of BCRP, OATP2B1 and other MDR transporters.
OBJECTIVE
To determine the role of BCRP in nitrofurantoin (NF) transport in JAr cells and the possible contribution of OATP2B1, P-gp and MRPs to this transport.


METHODS
Cells were incubated with various BCRP, P-gp, MRPs, organic anion transporting polypeptide (OAT) and OATP2B1 inhibitors for 15 min, followed by incubation for 30 min with NF, with or without the inhibitors mentioned earlier. NF cytotoxicity was examined using neutral red (NR) assay. Intracellular NF levels were analyzed by HPLC.


RESULTS
NR assay showed that incubation conditions with NF (as carried out in our experiments) were not cytotoxic. Incubation with specific inhibitors of BCRP (FTC, Chrysin and Novobiocin), showed a significant increase in NF accumulation in the cells. Inhibitors of OATP2B1 (EGCG and BSP) had no influence on NF accumulation. Specific inhibitors of P-gp and MRPs (Verapamil and Indomethacin, respectively) also had no influence on NF accumulation in JAr cells.


CONCLUSIONS
NF is probably a specific substrate of BCRP, and BCRP has a major active role in NF transport in JAr cells. For the first time, we showed, that P-gp, MRPs, and the OATP2B1, probably have a negligible contribution to NF transport in JAr cells.
Feinshtein
Valeria
V
Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Holcberg
Gershon
G
Amash
Alaa
A
Erez
Noam
N
Rubin
Mazal
M
Sheiner
Eyal
E
Polachek
Hana
H
Ben-Zvi
Zvi
Z
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000378:metabolism*; D005260:Female; D006801:Humans; D026901:Membrane Transport Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism*; D009582:Nitrofurantoin / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D014594:Uterine Neoplasms / Q000378:metabolism
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; C450859:SLCO2B1 protein, human; D009582:Nitrofurantoin