Chishu T, Sai Y, Nishimura T, Sato K, Kose N, Nakashima E
Department of Pharmaceutics, Kyoritsu University of Pharmacy, 1-5-30 Shiba-koen, Minato-ku, Tokyo 105-8512, Japan.
Placenta. 2008 May;29(5):461-7. doi: 10.1016/j.placenta.2008.01.010. Epub 2008 Mar 10.
The placenta requires nucleosides as nutrients for fetal growth, so it is important to examine potential interactions between placental transports of nucleosides and drugs to ensure the safety of pharmacotherapy during pregnancy. The purposes of this study are to clarify the uptake mechanisms of nucleosides from the maternal side of the syncytiotrophoblast and to investigate the inhibitory effect of various drugs on nucleoside uptake, using the rat syncytiotrophoblast cell line TR-TBT 18d-1, which shows syncytial-like morphology and functional expression of several transporters. Initial uptake of [(3)H]uridine or [(3)H]adenosine from the apical side of TR-TBT 18d-1 was markedly reduced by an excess of the respective unlabelled compound, and was slightly reduced by replacement of Na(+) with N-methyl-d-glucamine, indicating that both uptakes were Na(+)-independent. [(3)H]Uridine and [(3)H]adenosine uptakes in the absence of Na(+) were significantly and concentration-dependently inhibited by both 0.1 microM and 100 microM nitrobenzylthioinosine, suggesting the involvement of equilibrative nucleoside transporters (ENTs, SLC29). Kinetic analysis of adenosine uptake yielded a K(m) value of approximately 17 microM. These results are consistent with the reported uptake characteristics of uridine and adenosine by ENT1 and ENT2. The uptakes were significantly reduced by high concentrations of several nucleoside drugs, including cytarabine, vidarabine, zidovudine, mizoribine, caffeine and amitriptyline, but the effects were small within the therapeutic concentration ranges. In summary, our results suggest that ENTs are involved in apical uptake of uridine and adenosine in the syncytiotrophoblast. However, therapeutic concentrations of the drugs tested in this study might have little influence on maternal-to-fetal nucleoside transfer.
胎盘需要核苷作为胎儿生长的营养物质，因此研究核苷的胎盘转运与药物之间的潜在相互作用对于确保孕期药物治疗的安全性很重要。本研究的目的是利用大鼠合体滋养层细胞系TR-TBT 18d-1，阐明核苷从合体滋养层母体侧的摄取机制，并研究各种药物对核苷摄取的抑制作用，该细胞系表现出合体样形态和几种转运蛋白的功能表达。TR-TBT 18d-1顶端侧对[(3)H]尿苷或[(3)H]腺苷的初始摄取，会因过量的相应未标记化合物而显著降低，并且用N-甲基-D-葡糖胺替代Na(+)会使其略有降低，这表明两种摄取均不依赖于Na(+)。在无Na(+)的情况下，[(3)H]尿苷和[(3)H]腺苷的摄取均受到0.1 microM和100 microM硝基苄硫肌苷的显著且浓度依赖性抑制，提示平衡核苷转运体（ENTs，SLC29）参与其中。腺苷摄取的动力学分析得出K(m)值约为17 microM。这些结果与ENT1和ENT2对尿苷和腺苷的摄取特征报道一致。几种核苷类药物（包括阿糖胞苷、阿糖腺苷、齐多夫定、米唑立宾、咖啡因和阿米替林）的高浓度会显著降低摄取，但在治疗浓度范围内影响较小。总之，我们的结果表明ENTs参与了合体滋养层中尿苷和腺苷的顶端摄取。然而，本研究中测试药物的治疗浓度可能对母体到胎儿的核苷转运影响很小。
