Human placental transport of vinblastine, vincristine, digoxin and progesterone: contribution of P-glycoprotein

• Published in: European journal of pharmacology 2000-11, Vol.408 (1), p.1-10
• Main Authors: Ushigome, Fumihiko, Takanaga, Hitomi, Matsuo, Hirotami, Yanai, Shigeaki, Tsukimori, Kiyomi, Nakano, Hitoo, Uchiumi, Takeshi, Nakamura, Takanori, Kuwano, Michihiko, Ohtani, Hisakazu, Sawada, Yasufumi
• Format: Article
• Language: English
• Subjects: Antimetabolites - pharmacology; Antineoplastic Agents, Phytogenic - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; BeWo cells; Biological and medical sciences; Biological Transport, Active; Blood–placental barrier; Calcium Channel Blockers - pharmacology; Cardiotonic Agents - metabolism; Cell Line; Digoxin - metabolism; Drug disposition; Female; General pharmacology; Humans; Immunosuppressive Agents - pharmacology; Indicators and Reagents; Medical sciences; Microvilli - metabolism; P-Glycoprotein; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Placenta; Placenta - metabolism; Pregnancy; Progesterone - metabolism; Progesterone - pharmacology; Trophoblasts - metabolism; Vinblastine - metabolism; Vincristine - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00743-3

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 [ 3H]vinblastine and [ 3H]vincristine into BeWo cells was increased in the presence of a metabolic inhibitor, sodium azide. The basolateral-to-apical transcellular transport of [ 3H]vinblastine, [ 3H]vincristine and [ 3H]digoxin was greater than the apical-to-basolateral transcellular transport. In the presence of cyclosporin A, the basolateral-to-apical transcellular transport of [ 3H]vinblastine, [ 3H]vincristine and [ 3H]digoxin was significantly increased, and the apical-to-basolateral transcellular transport was decreased. The uptake of [ 3H]vinblastine, [ 3H]vincristine and [ 3H]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 [ 3H]vinblastine, [ 3H]vincristine and [ 3H]digoxin into BeWo cells, the uptake of [ 3H]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.