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Mrp4 Confers Resistance to Topotecan and Protects the Brain from Chemotherapy

机译：Mrp4赋予对拓扑替康的抗性并保护大脑免受化学疗法的侵害

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摘要

The role of the multidrug resistance protein MRP4/ABCC4 in vivo remains undefined. To explore this role, we generated Mrp4-deficient mice. Unexpectedly, these mice showed enhanced accumulation of the anticancer agent topotecan in brain tissue and cerebrospinal fluid (CSF). Further studies demonstrated that topotecan was an Mrp4 substrate and that cells overexpressing Mrp4 were resistant to its cytotoxic effects. We then used new antibodies to discover that Mrp4 is unique among the anionic ATP-dependent transporters in its dual localization at the basolateral membrane of the choroid plexus epithelium and in the apical membrane of the endothelial cells of the brain capillaries. Microdialysis sampling of ventricular CSF demonstrated that localization of Mrp4 at the choroid epithelium is integral to its function in limiting drug penetration into the CSF. The topotecan resistance of cells overexpressing Mrp4 and the polarized expression of Mrp4 in the choroid plexus and brain capillary endothelial cells indicate that Mrp4 has a dual role in protecting the brain from cytotoxins and suggest that the therapeutic efficacy of central nervous system-directed drugs that are Mrp4 substrates may be improved by developing Mrp4 inhibitors.
机译：尚不清楚在体内多药抗性蛋白MRP4 / ABCC4的作用。为了探索这一作用，我们产生了Mrp4缺陷小鼠。出乎意料的是，这些小鼠显示出抗癌药拓扑替康在脑组织和脑脊液（CSF）中的积累增强。进一步的研究表明，拓扑替康是Mrp4的底物，过表达Mrp4的细胞对其细胞毒性作用具有抗性。然后，我们使用新的抗体来发现Mrp4在阴离子ATP依赖的转运蛋白中是独特的，其双重定位是在脉络丛上皮的基底外侧膜和脑毛细血管内皮细胞的顶膜中。心室CSF的微透析采样显示，Mrp4在脉络膜上皮细胞的定位是其限制药物渗透到CSF中的功能所不可或缺的。在脉络丛和脑毛细血管内皮细胞中过表达Mrp4的细胞对拓扑替康的耐药性以及Mrp4的极化表达表明Mrp4在保护大脑免受细胞毒素的侵害中起着双重作用，并表明中枢神经系统定向药物的治疗功效是通过开发Mrp4抑制剂可以改善Mrp4底物。

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