TY - JOUR
T1 - Contribution of equilibrative nucleoside transporter (ENT) 2 to fluorouracil transport in rat placental trophoblast cells
AU - Takagi, Akinori
AU - Nishimura, Tomohiro
AU - Akashi, Tomoya
AU - Tomi, Masatoshi
AU - Nakashima, Emi
N1 - Funding Information:
This study was supported in part by JSPS KAKENHI Grant Numbers 15K15007, 15K08595, and 26282028. It was also funded in part by the MEXT-Supported Program for Strategic Research at Private Universities, the Food Safety Commission of Japan (Cabinet Office) (#1107), Takeda Science Foundation, The Uehara Memorial Foundation, Suzuken Memorial Foundation.
Publisher Copyright:
© 2016 The Japanese Society for the Study of Xenobiotics
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Fluorouracil is used for treatment of breast cancer even in pregnant women, except during fetal organogenesis. The purpose of this study was to clarify the transport mechanism of fluorouracil at the rat placental barrier. Maternal-to-fetal transfer of [3H]fluorouracil in rats at gestational day 19.5 was saturable and much higher than that of [14C]sucrose. The uptake of [3H]fluorouracil was also saturable in rat placental trophoblast TR-TBT 18d-1 cells, which express both equilibrative nucleoside transporter (ENT) 1 and ENT2. Nitrobenzylthioinosine (NBMPR) at 0.1 μM had no effect on [3H]fluorouracil uptake by TR-TBT 18d-1 cells, but 100 μM NBMPR almost completely inhibited the saturable component, suggesting involvement of ENT2, rather than ENT1 in the transport. Rat ENT2 cRNA-injected oocytes showed significantly increased [3H]fluorouracil uptake compared with water-injected oocytes, while rat ENT1 cRNA-injected oocytes did not show an increase of [3H]fluorouracil uptake. The Michaelis–Menten constant for rat ENT2-mediated uptake of [3H]fluorouracil was 4.21 mM. The expression profile of ENT2 mRNA in rat placenta during pregnancy was almost constant from 13.5 to 21.5 days of gestation. In conclusion, ENT2 appears to be the mediator of fluorouracil transport in rat placental trophoblast cells.
AB - Fluorouracil is used for treatment of breast cancer even in pregnant women, except during fetal organogenesis. The purpose of this study was to clarify the transport mechanism of fluorouracil at the rat placental barrier. Maternal-to-fetal transfer of [3H]fluorouracil in rats at gestational day 19.5 was saturable and much higher than that of [14C]sucrose. The uptake of [3H]fluorouracil was also saturable in rat placental trophoblast TR-TBT 18d-1 cells, which express both equilibrative nucleoside transporter (ENT) 1 and ENT2. Nitrobenzylthioinosine (NBMPR) at 0.1 μM had no effect on [3H]fluorouracil uptake by TR-TBT 18d-1 cells, but 100 μM NBMPR almost completely inhibited the saturable component, suggesting involvement of ENT2, rather than ENT1 in the transport. Rat ENT2 cRNA-injected oocytes showed significantly increased [3H]fluorouracil uptake compared with water-injected oocytes, while rat ENT1 cRNA-injected oocytes did not show an increase of [3H]fluorouracil uptake. The Michaelis–Menten constant for rat ENT2-mediated uptake of [3H]fluorouracil was 4.21 mM. The expression profile of ENT2 mRNA in rat placenta during pregnancy was almost constant from 13.5 to 21.5 days of gestation. In conclusion, ENT2 appears to be the mediator of fluorouracil transport in rat placental trophoblast cells.
KW - ENT
KW - Fluorouracil
KW - Placental barrier
KW - Syncytiotrophoblasts
KW - Transporter
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U2 - 10.1016/j.dmpk.2016.12.001
DO - 10.1016/j.dmpk.2016.12.001
M3 - Article
C2 - 28209435
AN - SCOPUS:85012885293
SN - 1347-4367
VL - 32
SP - 151
EP - 156
JO - Drug Metabolism And Pharmacokinetics
JF - Drug Metabolism And Pharmacokinetics
IS - 2
ER -
