Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)mediated efflux of cAMP and resistance to purine analogues
Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)mediated efflux of cAMP and resistance to purine analogues
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DOI：
10.1042/0264-6021:3610497
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发表时间：
2002-02-01
影响因子：
4.1
通讯作者：
Tan, TM
中科院分区：
文献类型：
--
作者：
Lai, LQ;Tan, TM
多药耐药蛋白4（MRP 4/ABCC 4）是MRP亚家族的成员，MRP亚家族又是ATP结合盒（ABC）转运蛋白超家族的成员。在MRP亚家族中，ABCC 4、ABCC 5（MRP 5）、ABCC 11（MRP 8）和ABCC 12（MRP 9）具有相似的预测膜拓扑结构。所有这些都缺乏额外的跨膜结构域，TMD，这是存在于其他MRP。使用稳定过表达ABCC 4的细胞，该研究表明ABCC 4输出GSH。ABCC 4还促进cAMP的流出。用DL-丁硫氨酸-（S，R）-磺酰亚胺耗尽细胞内GSH导致cAMP输出减少，并观察到细胞内cAMP相应增加。ABCC 4还介导对嘌呤类似物9-（2-膦酰基甲氧基乙基）-腺嘌呤和6-硫代鸟嘌呤的抗性。这种耐药性可以通过DL-丁硫氨酸-（S，R）-磺酰亚胺的存在而逆转。我们的结论是，以及核苷酸和核苷类似物，ABCC 4可以介导的GSH的输出。此外，GSH在ABCC 4的功能中起重要作用。细胞内GSH的消耗不利地影响ABCC 4对CAMP的输出。对核苷类似物的抗性也受到细胞GSH耗尽的不利影响。
Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4, ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD, which is present in the other MRPs. Using cells stably overexpressing ABCC4, this study shows that ABCC4 exports GSH. ABCC4 also facilitates the efflux of cAMP. Depletion of intracellular GSH with DL-buthionine-(S,R)-sulphoximine led to decreased export of cAMP and a corresponding increase in intracellular cAMP was observed. ABCC4 also mediates resistance to purine analogues 9-(2-phosphonylmethoxyethyl)-adenine and 6-thioguanine. This resistance can be reversed by the presence of DL-buthionine-(S,R)-sulphoximine. We conclude that as well as nucleotide and nucleoside analogues, ABCC4 can mediate the export of GSH. In addition, GSH plays an important role in the function of ABCC4. Depletion of intracellular GSH adversely affects the export of CAMP by ABCC4. Resistance to nucleoside analogues is also adversely affected by depletion of cellular GSH.