UPTAKE OF DIAMIDINE DRUGS BY THE P2 NUCLEOSIDE TRANSPORTER IN MELARSEN-SENSITIVE AND -RESISTANT TRYPANOSOMA-BRUCEI-BRUCEI
UPTAKE OF DIAMIDINE DRUGS BY THE P2 NUCLEOSIDE TRANSPORTER IN MELARSEN-SENSITIVE AND -RESISTANT TRYPANOSOMA-BRUCEI-BRUCEI
复制标题
DOI：
10.1074/jbc.270.47.28153
复制
发表时间：
1995-11-24
影响因子：
4.8
通讯作者：
FAIRLAMB, AH
中科院分区：
文献类型：
--
作者：
CARTER, NS;BERGER, BJ;FAIRLAMB, AH
非洲锥虫布氏锥虫至少具有两个核苷转运体系统，分别命名为P1和P2，后者与三聚氰胺苯砷类药物的选择性摄取有关。由于抗砷锥虫在体内对芳香族二脒类药物表现出交叉耐药性，我们研究了这些药物是否也是P2核苷转运体的底物。B.布氏锥虫中，二脒类药物，包括常用的锥虫药，喷他脒和Berenil，被发现在体外消除由氧化米拉森的P2转运诱导的溶解。B.布氏杆菌，证明摄取是载体介导的，Km为0.84 μ M，V-max为9.35 pmol s（-1）（10（8）个细胞）（-1）。在这些细胞中，喷他脒转运似乎是P2介导的，因为喷他脒强烈抑制P2转运蛋白对[2 ′，5 ′，8-H-3]腺苷的摄取，Ki为0.56 μ M。此外，[环-H-3]喷他脒转运被许多P2转运蛋白底物和抑制剂以及其它联脒药物阻断，在体外和体内，这也表明这些化合物在体内的差异水平的耐药性，耐美拉砷锥虫的pentamidine和其他diamidines的摄取分析表明，P2的运输在这些细胞中被改变，这些药物的积累显着减少。
The African trypanosome, Trypanosoma brucei brucei, possesses at least two nucleoside transporter systems designated P1 and P2, the latter being implicated in the selective uptake of melaminophenyl arsenical drugs, Since arsenical-resistant trypanosomes show cross-resistance in vivo to aromatic diamidines, we have investigated whether these drugs are also substrates for the P2 nucleoside transporter, In melarsen-sensitive T. b. brucei, the diamidines, including the commonly used trypanocides, pentamidine and berenil, were found to abrogate lysis induced by the P2 transport of melarsen oxide in vitro, Measurement of [ring-H-3]pentamidine transport in melarsen-sensitive T. b. brucei, demonstrated that uptake is carrier-mediated, with a K-m of 0.84 mu M and a V-max of 9.35 pmol s(-1) (10(8) cells)(-1). Pentamidine transport appears to be P2-mediated in these cells, as pentamidine strongly inhibited uptake of [2',5',8-H-3]adenosine by the P2 transporter, with a K-i of 0.56 mu M, Furthermore, [ring-H-3]pentamidine transport was blocked by a number of P2 transporter substrates and inhibitors, as well as by other diamidine drugs, Analysis of the uptake of pentamidine and other diamidines in melarsen-resistant trypanosomes in vitro and in vivo, which also show differential levels of resistance to these compounds in vivo, indicated that P2 transport was altered in these cells and that accumulation of these drugs was markedly reduced.