Howard E M, Zhang H, Roepe P D
Dept. of Chemistry, Dept. of Biochemistry and Molecular Biology, Lombardi Cancer Center, Georgetown University, 37th and O Streets, Washington, DC 20057-1227, USA.
J Membr Biol. 2002 Nov 1;190(1):1-8. doi: 10.1007/s00232-002-1019-3.
The elucidation of the molecular details of drug resistance phenomena is a very active area of research that crosses many disciplinary boundaries. Drug resistance is due to altered drug-target interaction, and/or dysregulated signaling related to cell growth and death. Since many drugs need to rapidly diffuse into and within cells in order to find their targets, and since transmembrane ion transport is an important facet of cellular signaling, it is not surprising that membrane transport phenomena have been implicated in the evolution of drug resistance in tumor cells, bacteria, and intracellular parasites such as Plasmodium falciparum, the causative agent of the most lethal form of human malaria. The most infamous membrane transport protein involved in drug resistance is "MDR protein" or "P-glycoprotein" (Pgp),1 which was found to be overexpressed in drug-resistant tumor cells over 15 years ago, and which is representative of the ATP-binding cassette (ABC) superfamily that also includes the important cystic fibrosis transmembrane conductance regulator (CFTR) and sulfonyl urea receptor (SUR) ion channels. Availability of mouse and human Pgp cDNA rather quickly led to the identification of homologues in many species, including P. falciparum, and these were de facto assumed to be the ultimate determinants of drug resistance in these systems as well. However, research over the past 10 years has taught us that this assumption likely is wrong and that the situation is more complex. We now know that human Pgp plays a relatively minor role in clinically relevant tumor drug resistance, and that an integral membrane protein with no homology to the ABC superfamily, Pfcrt, ultimately confers chloroquine resistance in P. falciparum. Thus, the general hypothesis that membrane transport and membrane transport proteins are important in drug resistance phenomena remains correct, but at a genetic, biochemical, and physiological level we have recently witnessed a few very interesting surprises.
耐药现象分子细节的阐明是一个非常活跃的研究领域，跨越了许多学科界限。耐药性是由于药物与靶点相互作用的改变，和/或与细胞生长和死亡相关的信号传导失调。由于许多药物需要迅速扩散进入细胞并在细胞内移动以找到它们的靶点，并且由于跨膜离子转运是细胞信号传导的一个重要方面，因此膜转运现象与肿瘤细胞、细菌以及细胞内寄生虫（如恶性疟原虫，最致命形式的人类疟疾的病原体）耐药性的演变有关也就不足为奇了。参与耐药性的最臭名昭著的膜转运蛋白是“多药耐药蛋白”或“P-糖蛋白”（Pgp），1 它在 15 多年前就被发现在耐药肿瘤细胞中过度表达，并且是 ATP 结合盒（ABC）超家族的代表，该超家族还包括重要的囊性纤维化跨膜电导调节因子（CFTR）和磺脲类受体（SUR）离子通道。小鼠和人类 Pgp cDNA 的可得性很快导致在许多物种中鉴定出同源物，包括恶性疟原虫，并且事实上这些也被认为是这些系统中耐药性的最终决定因素。然而，过去 10 年的研究告诉我们，这个假设可能是错误的，情况更加复杂。我们现在知道，人类 Pgp 在临床相关的肿瘤耐药性中起相对较小的作用，并且一种与 ABC 超家族无同源性的整合膜蛋白 Pfcrt 最终赋予恶性疟原虫对氯喹的耐药性。因此，膜转运和膜转运蛋白在耐药现象中很重要这一普遍假设仍然正确，但在基因、生化和生理水平上，我们最近见证了一些非常有趣的意外发现。
