Kinetics of anthracycline efflux from multidrug resistance protein-expressing cancer cells compared with P-glycoprotein-expressing cancer cells
Kinetics of anthracycline efflux from multidrug resistance protein-expressing cancer cells compared with P-glycoprotein-expressing cancer cells
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DOI：
10.1124/mol.53.1.141
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发表时间：
1998-01-01
影响因子：
3.6
通讯作者：
Garnier-Suillerot, A
中科院分区：
文献类型：
--
作者：
Marbeuf-Gueye, C;Broxterman, HJ;Garnier-Suillerot, A
多药耐药蛋白（MRP）介导了多种结构的抗癌药物（如柔红霉素（DNR）、长春新碱和依托泊苷）的ATP依赖性外排。因此，这种蛋白质确实赋予癌细胞多药耐药表型，类似于P-糖蛋白（Pgp）。两种转运蛋白的底物特异性部分重叠，但在其他方面非常不同;因为MRP是一种多有机阴离子转运蛋白，它转运某些谷胱甘肽结合物，并且可能部分依赖于蒽环类药物转运的细胞内谷胱甘肽水平。我们研究了一系列蒽环类药物在MRP和Pgp过表达肿瘤细胞系中的转运动力学，以获得这些蛋白质底物特异性的信息。蒽环类药物在糖部分有修饰。用于表征主动外排效率的平均主动外排系数k（α）对于MRP和Pgp的DNR及其4 ′-脱氧衍生物之一（eso-DNR）非常相似[10-20 × 10（-10）/sec/（细胞/ml）]。永久中性衍生物3 ′-脱氨基-3 ′-羟基-阿霉素（OH-DOX）和3 ′-脱氨基-3 ′-羟基-柔红霉素（OH-DNR）被两种蛋白质外排，但具有较低的k（a），[2 x 10（-10）和6 x 10（-10）/sec/（细胞/ml）（OH-DOX）和2 x 10（-10）和5 x 10（-10）/sec/（细胞/ml）（OH-DNR）]用于MRP和Pgp。两种蒽环类抗生素，阿霉素衍生物吡拉西坦和2 '-溴-4'-表-DNR似乎对Pgp的k（a）值略高于MRP。主动转运的表观Michaelis-Menten常数（K-m）和最大外排速率（V-M）在两种转运蛋白的狭窄范围内，但OH-DOX和OH-DNR除外，在MRP介导的转运中，其V-M较低，表明氨基在与谷胱甘肽相互作用中的作用。MRP介导的外排的希尔系数（n（H））的测定给出了接近2的大多数值，这表明如之前报道的Pgp的蒽环类药物转运的协同性。总之，MRP和Pgp对蒽环类药物的转运动力学非常相似。
The multidrug resistance protein (MRP) has been shown to mediate ATP-dependent efflux of anticancer agents of diverse structure, such as daunorubicin (DNR), vincristine and etoposide. Thus, this protein does confer a multidrug resistant phenotype to cancer cells, similar to P-glycoprotein (Pgp). The substrate specificity of both transporter proteins is partly overlapping but is otherwise very distinct; because MRP is a multiple organic anion transporter, it transports certain glutathione conjugates and may be partly dependent on intracellular glutathione levels for the transport of anthracyclines. We have studied the transport kinetics of a series of anthracyclines in MRP and Pgp that overexpress tumor cell lines to obtain information on the substrate specificity of these proteins. The anthracyclines have modifications in the sugar moiety. The mean active efflux coefficient k(a),, used to characterize the efficiency of the active efflux, was very similar for DNR and one of its 4'-deoxy-derivatives (eso-DNR) for MRP and Pgp [10-20 x 10(-10)/sec/(cells/ml)l. The permanently neutral derivatives 3'-deamino-3'-hydroxy-doxorubicin (OH-DOX) and 3'-deamino-3'-hydroxy-daunorubicin (OH-DNR) were effluxed by both proteins but had a lower k(a), [2 x 10(-10) and 6 x 10(-10)/sec/(cells/ml) (OH-DOX) and 2 x 10(-10) and 5 x 10(-10)/sec/(cells/ml) (OH-DNR)] for MRP and Pgp. Two anthracyclines, the doxorubicin derivative pirarubicin and 2'-bromo-4'-epi-DNR seemed to have a slightly higher k(a), value for Pgp than for MRP. The apparent Michaelis-Menten constants (K-m,) and maximal efflux rates (V-M) for the active transport were within a narrow range for both transporters, except for OH-DOX and OH-DNR, which had a lower V-M, in the case of MRP-mediated transport, suggesting a role of the amino group in the interaction with glutathione. Determination of the Hill coefficient (n(H)) of the MRP-mediated efflux gave most values close to 2, which suggests cooperativity of the transport of anthracyclines as reported before for Pgp. In conclusion, the transport kinetics of anthracyclines by MRP and Pgp are very similar.