Mechanism of Nucleoside Uptake in Rat Placenta and Induction of Placental CNT2 in Experimental Diabetes

• Published in: DRUG METABOLISM AND PHARMACOKINETICS Vol. 27; no. 4; pp. 439 - 446
• Main Authors: Nishimura, Tomohiro, Chishu, Takuya, Tomi, Masatoshi, Nakamura, Ryo, Sato, Kazuko, Kose, Noriko, Sai, Yoshimichi, Nakashima, Emi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 2012; Japanese Society for the Study of Xenobiotics
• Subjects: Adenosine - metabolism; Animals; antivirals; Biological Transport; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - genetics; Carrier Proteins - metabolism; diabetes; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Diabetes, Gestational - chemically induced; Diabetes, Gestational - genetics; Diabetes, Gestational - metabolism; drug distribution; Equilibrative-Nucleoside Transporter 2 - antagonists & inhibitors; Equilibrative-Nucleoside Transporter 2 - genetics; Equilibrative-Nucleoside Transporter 2 - metabolism; Female; Maternal-Fetal Exchange; membrane permeability; Membrane Transport Proteins - metabolism; Microvilli - metabolism; nucleosides; Nucleosides - blood; Nucleosides - metabolism; Nucleosides - pharmacokinetics; Oocytes; placenta; Placenta - metabolism; Placenta - ultrastructure; Pregnancy; Rats; Rats, Wistar; RNA, Messenger - metabolism; SLC28; SLC29; Thioinosine - analogs & derivatives; Thioinosine - pharmacology; transporters; Trophoblasts - metabolism; Trophoblasts - ultrastructure; Up-Regulation; Xenopus laevis; Zidovudine - metabolism; antivirals; nucleosides; transporters; SLC29; SLC28; membrane permeability; drug distribution; placenta; diabetes
• ISSN: 1347-4367; 1880-0920
• DOI: 10.2133/dmpk.DMPK-11-RG-103

The purpose of this study was to clarify the transport characteristics of nucleosides in rat placenta and the changes of functional expression of nucleoside transporters in rat placenta with experimental diabetes mellitus. Placental uptake clearances of [3H]adenosine and [3H]zidovudine from maternal blood was much higher than that of [14C]mannitol. Xenopus oocytes injected with rat ENT1 and ENT2 cRNA took up [3H]adenosine with Km values of 6.1 and 26 μΜ, respectively. [3H]Adenosine transport by rat placental brush-border membrane vesicles (BBMV) was saturable and was inhibited by nitro- benzylthioinosine (NBMPR), a specific ENT inhibitor, in a manner consistent with involvement of both rat ENT1 and ENT2. [3H]Didanosine was modestly taken up by placenta, and the inhibitory effect of 100 μΜ NBMPR on [3H]ddI uptake by BBMV suggested a role of ENT2-mediated transport. Expression of ENT1, ENT2, ENT3, CNT2, and CNT3 mRNAs was detected in placenta of control and streptozotocin (STZ)- induced diabetic pregnant rats, and CNT2 (SLC28A2) expression was significantly increased in STZ- induced diabetic rats. Consistently, Na+−dependent adenosine uptake by BBMV from STZ-induced diabetic pregnant rats was higher than that from control rats. These results suggest the involvement of placental ENT2 as well as ENT1 in nucleoside uptake from maternal blood, and the induction of CNT2 in experimental diabetes mellitus.