PDS STUDY ON HUMAN PGP MDR TRANSPORTER ABCB1

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 P-糖蛋白（Pgp，ABCB 1）是由多药耐药基因1（multidrug resistance 1，MDR 1）编码的一种哺乳动物质膜磷酸化糖蛋白，属于ATP结合盒转运蛋白超家族。Pgp在肿瘤对细胞毒性药物的抗性中起作用，并且已知其从细胞中排出结构上不相关的多种两亲化合物。Pgp在多药耐药癌细胞和许多正常组织中表达，如肝、肾、小肠、结肠和脑，这表明Pgp的生理作用是对外源性物质和内源性代谢物的保护机制。在暴露于单一细胞毒性药物（例如一种生物碱、蒽环类、紫杉烷类或放线菌素D）后，细胞可以过表达Pgp并表现出MDR表型。Pgp的过度表达不仅是由化学物质诱导的，也可以由X射线和紫外线照射引起的物理应激或热休克诱导。大约50%的目前上市的药物已被确定为Pgp底物和/或抑制剂。Pgp可通过促进控制吸收、分布、代谢、消除和/或毒性（ADMET）的过程来影响药物的药代动力学。此外，Pgp还涉及药物间相互作用，涉及共同给药的Pgp底物和调节剂。例如，肠Pgp介导包括紫杉醇在内的药物的大量直接经上皮排泄。ABCB 1不是寡聚体，而是与二聚体原核ABC转运蛋白同源，如MsbA，其已在ACERT通过Ku-带DEER成功研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. P-glycoprotein (Pgp, ABCB1), which belongs to the ATP-binding cassette (ABC) transporter superfamily, is a mammalian plasma membrane phospho-glycoprotein encoded by the multidrug resistance 1 (MDR1) gene. Pgp plays a role in the resistance of tumors to cytotoxic drugs and is known to efflux structurally unrelated diverse amphipathic compounds from cells. Pgp is expressed both in multidrug-resistant cancer cells and also in a number of normal tissues, such as those of the liver, kidney, small intestine, colon, and brain, suggesting that the physiological role of Pgp is a protective mechanism against xenobiotics and endogenous metabolites. After exposure to a single cytotoxic drug such as one of the Vinca alkaloids, anthracyclines, taxoids, or actinomycin D, cells can over-express Pgp and exhibit the MDR phenotype. Pgp over-expression is induced not only by chemical compounds, but also by physical stress caused by X-rays and ultraviolet light irradiation, or heat shock. Approximately 50% of currently marketed drugs have been identified to be Pgp substrates and/or inhibitors. Pgp can influence the pharmacokinetics of drugs by contributing to the processes that govern absorption, distribution, metabolism, elimination, and/or toxicity (ADMET). Additionally, Pgp has been implicated in drug-drug interactions involving co-administered Pgp substrates and modulators. For instance, intestinal Pgp mediates substantial direct transepithelial excretion of drugs including paclitaxel. ABCB1 is not oligomeric, but is homologous to dimeric prokaryotic ABC transporters, such as MsbA, which has been successfully studied at ACERT by Ku-band DEER.