6-Mercaptopurine transport by equilibrative nucleoside transporters in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBTs

Na young Lee, Yoshimichi Sai, Emi Nakashima, Sumio Ohtsuki, Young sook Kang

研究成果: Article査読

14 被引用数 (Scopus)

抄録

Recently, more women were provided with 6-mercaptopurine (6-MP) during pregnancy. Therefore, we attempted to clarify the transport mechanisms of 6-MP through blood-placenta barrier using rat conditionally immortalized syncytiotrophoblast cell lines (TR-TBTs). The uptake of 6-MP was time- and ATP dependent, but sodium independent in TR-TBTs. 6-MP was eliminated over 50% from the cells within 30min. The uptake of 6-MP was saturable with Michaelis-Menten constant values of 198μM and 250μM in TR-TBT 18d-1 and TR-TBT 18d-2, respectively. 6-Thioguanine, azathioprine, and hypoxantine, structural analogues of 6-MP, strongly inhibited [14C]6-MP uptake. Equilibrative nucleoside transporter (ENT) inhibitors, adenosine and uridine, significantly inhibited [14C]6-MP uptake. However, several organic anions and cations had no effect on [14C]6-MP uptake in TR-TBTs. These results suggest that sodium-independent transporters, ENTs, may be involved in 6-MP uptake at the placenta. In addition, multidrug resistance protein (MRP) inhibitors, methotrexate, probenecid, cefmetazole, and sulfinpyrazone, significantly increased the accumulation of [14C]6-MP in the cells. It is indicated that 6-MP may be eliminated across the blood-placental barrier via MRPs. TR-TBTs expressed mRNA of ENT1, ENT2, MRP4, and MRP5. These findings are important for the therapy of acute lymphoblastic leukemia and autoimmune diseases of pregnant women, and should be useful data in elucidating teratogenicity of 6-MP during pregnancy.

本文言語English
ページ(範囲)3773-3782
ページ数10
ジャーナルJournal of Pharmaceutical Sciences
100
9
DOI
出版ステータスPublished - 2011 9

ASJC Scopus subject areas

  • 薬科学

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