Higgins Christopher F
MRC Clinical Sciences Centre, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
Nature. 2007 Apr 12;446(7137):749-57. doi: 10.1038/nature05630.
The acquisition of multidrug resistance is a serious impediment to improved healthcare. Multidrug resistance is most frequently due to active transporters that pump a broad spectrum of chemically distinct, cytotoxic molecules out of cells, including antibiotics, antimalarials, herbicides and cancer chemotherapeutics in humans. The paradigm multidrug transporter, mammalian P-glycoprotein, was identified 30 years ago. Nonetheless, success in overcoming or circumventing multidrug resistance in a clinical setting has been modest. Recent structural and biochemical data for several multidrug transporters now provide mechanistic insights into how they work. Organisms have evolved several elegant solutions to ridding the cell of such cytotoxic compounds. Answers are emerging to questions such as how multispecificity for different drugs is achieved, why multidrug resistance arises so readily, and what chance there is of devising a clinical solution.
多重耐药性的产生是改善医疗保健的严重障碍。多重耐药性最常见的原因是主动转运蛋白，这些蛋白将多种化学性质不同的细胞毒性分子泵出细胞，包括人类的抗生素、抗疟药、除草剂和癌症化疗药物。典型的多重耐药转运蛋白——哺乳动物P-糖蛋白，是在30年前被鉴定出来的。尽管如此，在临床环境中克服或规避多重耐药性方面所取得的成功一直有限。最近关于几种多重耐药转运蛋白的结构和生化数据，现在为它们的工作机制提供了深入了解。生物体已经进化出几种巧妙的方法来清除细胞中的此类细胞毒性化合物。对于诸如如何实现对不同药物的多特异性、为什么多重耐药性如此容易出现以及设计临床解决方案的可能性等问题，答案正在浮现。
