Decreased intracellular compartmentalization of doxorubicin in cell lines expressing P-glycoprotein.
Decreased intracellular compartmentalization of doxorubicin in cell lines expressing P-glycoprotein.
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发表时间：
1994-12
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通讯作者：
M. Dordal;M. Jackson-Stone;A. C. Ho;J. Winter;A. Atkinson
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作者：
M. Dordal;M. Jackson-Stone;A. C. Ho;J. Winter;A. Atkinson
[14 C]阿霉素最初快速分布到药物敏感的HL-60和SU-4细胞后，缓慢摄取持续4小时以上，占细胞内药物总量的80%。相反，在表达P-糖蛋白的耐药HL-60 R和SU-4 R细胞中，阿霉素分布迅速接近平衡。这种行为的最简单的动力学模型包括从细胞外液快速扩散到细胞中，然后被吸收到不可交换的细胞内池中。在3.4 μ M多柔比星时，所有细胞系的跨膜扩散清除率相似（0.78-0.98 μ L sec-1）。在P-糖蛋白表达细胞系中，标准化表观分布容积没有降低，如果存在主动单向外排，则会出现预期的降低。然而，在耐药细胞中，多柔比星在不可交换池中的蓄积比敏感细胞慢15倍（HL-60 R vs. HL-60中为0.004 vs. 0.050 μ l sec-1; SU-4 R vs. SU-4中为0.004 vs. 0.058 μ l sec-1）。在0 ℃下暴露于阿霉素的SU-4或SU-4 R细胞中均未检测到池流入，表明不可交换的积累需要能量。在SU-4 R细胞中，在20 μ M多柔比星时，阻止蓄积的过程开始饱和，而在HL-60 R中没有观察到饱和的证据，HL-60 R比SU-4 R具有更高的抗性。我们建议，改变区室化是主要负责在这些细胞系中观察到的阿霉素耐药性。
After initial rapid [14C]doxorubicin distribution into drug-sensitive HL-60 and SU-4 cells, slow uptake continues for more than 4 hr, accounting for up to 80% of the total intracellular drug. In contrast, in P-glycoprotein-expressing drug-resistant HL-60R and SU-4R cells, doxorubicin distribution rapidly approaches equilibrium. The simplest kinetic model of this behavior consists of rapid diffusion from extracellular fluid into the cell, followed by uptake into a nonexchangeable intracellular pool. At 3.4 microM doxorubicin, transmembrane diffusion clearance was similar for all cell lines (0.78-0.98 microliter sec-1). There was no decrease in the normalized apparent volume of distribution in the P-glycoprotein-expressing cell lines, as would be expected if an active, unidirectional efflux were present. However, in resistant cells, doxorubicin accumulation in the nonexchangeable pool was up to 15-fold slower than in sensitive cells (0.004 vs. 0.050 microliter sec-1 in HL-60R vs. HL-60; 0.004 vs. 0.058 microliter sec-1 in SU-4R vs. SU-4). No pool inflow could be detected in either SU-4 or SU-4R cells exposed to doxorubicin at 0 degrees C, indicating that the nonexchangeable accumulation requires energy. The process preventing accumulation began to saturate in SU-4R cells at 20 microM doxorubicin, whereas no evidence of saturation was seen with HL-60R, which is more highly resistant than SU4R. We propose that alteration in compartmentalization is primarily responsible for the doxorubicin resistance observed in these cell lines.