THE HUMAN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN MRP IS A PLASMA-MEMBRANE DRUG-EFFLUX PUMP
THE HUMAN MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN MRP IS A PLASMA-MEMBRANE DRUG-EFFLUX PUMP
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DOI：
10.1073/pnas.91.19.8822
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发表时间：
1994-09-13
影响因子：
11.1
通讯作者：
BORST, P
中科院分区：
文献类型：
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作者：
ZAMAN, GJR;FLENS, MJ;BORST, P
多药耐药相关蛋白MRP是一种180-195 kDa的膜蛋白，与人类肿瘤细胞对细胞毒药物的耐药性有关。我们研究了MRP是如何在人肺癌细胞系SW-1573中产生耐药的，方法是建立稳定地携带MRP基因表达载体的亚系。Mrp过表达的Sw-1573细胞对阿霉素、柔红霉素、长春新碱、VP-16、秋水仙碱和罗丹明123耐药，但对4‘-(9-acridinylamino)methanesulfon-m-anisidide和紫杉醇不耐药。药物(柔红霉素、长春新碱和VP-16)在细胞内的蓄积减少，药物(柔红霉素)的外流增加。洋地黄素对细胞质膜的通透性可以消除柔红霉素的减少积累，这表明MRP可以针对浓度梯度降低细胞内柔红霉素水平。抗MRP抗血清主要染色MRP高表达细胞的质膜。我们认为，MRP是一种质膜药物外排泵。
The multidrug-resistance associated protein MRP is a 180- to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an expression vector containing MRP cDNA. MRP-overexpressing SW-1573 cells are resistant to doxorubicin, daunorubicin, vincristine, VP-16, colchicine, and rhodamine 123, but not to 4'-(9-acridinylamino)methanesulfon-m-anisidide or taxol. The intracellular accumulation of drug (daunorubicin, vincristine, and VP-16) is decreased and the efflux of drug (daunorubicin) is increased in the transfectant. The decreased accumulation of daunorubicin is abolished by permeabilization of the plasma membrane with digitonin, showing that MRP can lower the intracellular daunorubicin level against a concentration gradient. Anti-MRP antisera predominantly stain the plasma membrane of MRP-overexpressing cells. We conclude that MRP is a plasma membrane drug-efflux pump.