Archives of gynecology and obstetrics · 2009
Nitrofurantoin transport by placental choriocarcinoma JAr cells: involvement of BCRP, OATP2B1 and other MDR transporters.
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Feinshtein Valeria, Holcberg Gershon, Amash Alaa, Erez Noam, Rubin Mazal, Sheiner Eyal, Polachek Hana, Ben-Zvi Zvi
Аннотация
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.
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.
Предметные рубрики MeSH
ATP Binding Cassette Transporter, Subfamily B, Member 1ATP Binding Cassette Transporter, Subfamily G, Member 2ATP-Binding Cassette TransportersCell Line, TumorChoriocarcinomaFemaleHumansMembrane Transport ProteinsNeoplasm ProteinsNitrofurantoinOrganic Anion TransportersPlacentaPregnancyUterine Neoplasms