Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein.
To elucidate the role of P-glycoprotein in human placenta, we examined its expression in placenta, and the transcellular transport and uptake of P-glycoprotein substrates in cultured human placental choriocarcinoma epithelial cells (BeWo cells). The uptake of [(3)H]vinblastine and [(3)H]vincristine into BeWo cells was increased in the presence of a metabolic inhibitor, sodium azide. The basolateral-to-apical transcellular transport of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin was greater than the apical-to-basolateral transcellular transport. In the presence of cyclosporin A, the basolateral-to-apical transcellular transport of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin was significantly increased, and the apical-to-basolateral transcellular transport was decreased. The uptake of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin into BeWo cells was significantly enhanced in the presence of several inhibitors, such as verapamil or mouse monoclonal antibody anti-P-glycoprotein MX-MDR (MRK16) as well as cyclosporin A. Although progesterone significantly enhanced the uptake of [(3)H]vinblastine, [(3)H]vincristine and [(3)H]digoxin into BeWo cells, the uptake of [(3)H]progesterone was not affected by these inhibitors. Immunoblot analysis revealed that P-glycoprotein with a molecular weight of 172 kDa was expressed in BeWo cells and isolated trophoblast cells. Furthermore, P-glycoprotein was detected in human placental brush-border membrane vesicles, but not in human placental basolateral membrane vesicles. In conclusion, these data suggest that P-glycoprotein is expressed on the brush-border membrane (maternal side) of human placental trophoblast cells. P-Glycoprotein is considered to regulate the transfer of several substances including vinblastine, vincristine and digoxin from mother to fetus, and to protect the fetus from toxic substances.
Ushigome
F
F
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Takanaga
H
H
Matsuo
H
H
Yanai
S
S
Tsukimori
K
K
Nakano
H
H
Uchiumi
T
T
Nakamura
T
T
Kuwano
M
M
Ohtani
H
H
Sawada
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000963:Antimetabolites / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001693:Biological Transport, Active; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000378:metabolism*; D002460:Cell Line; D004077:Digoxin / Q000378:metabolism*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D008871:Microvilli / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology; D014327:Trophoblasts / Q000378:metabolism; D014747:Vinblastine / Q000378:metabolism*; D014750:Vincristine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000963:Antimetabolites; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D011374:Progesterone; D014750:Vincristine; D014747:Vinblastine; D004077:Digoxin