PDS STUDY ON HUMAN PGP MDR TRANSPORTER ABCB1

人类 PGP MDR 转运蛋白 ABCB1 的 PDS 研究

• 批准号: 8364053
• 负责人: ELKA R GEORGIEVA
• 金额: $ 3.06万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364053
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Anthracyclines; Brain; Cell membrane; Cells; Chemicals; Colon; Cytotoxic agent; D Cells; Dactinomycin; Drug Interactions; Drug Kinetics; Excretory function; Exhibits; Exposure to; Funding; Glycoproteins; Grant; Heat-Shock Response; Human; Intestines; Kidney; Liver; Mediating; Metabolism; Multi-Drug Resistance; National Center for Research Resources; Normal tissue morphology; P-Glycoprotein; Paclitaxel; Pharmaceutical Preparations; Phenotype; Physiological; Play; Principal Investigator; Process; Research; Research Infrastructure; Resistance; Resources; Roentgen Rays; Role; Small Intestines; Source; Stress; Taxoids; Technology; Toxic effect; Ultraviolet Rays; United States National Institutes of Health; Vinca Alkaloids; Xenobiotics; absorption; cancer cell; cost; drug market; inhibitor/antagonist; irradiation; tumor

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 属于ATP结合盒（ABC）转运蛋白超家族的P-糖蛋白（PGP，ABCB1）是由多种耐药性1（MDR1）基因编码的哺乳动物质膜磷酸 - 糖蛋白。 PGP在肿瘤对细胞毒性药物的耐药性中起作用，并已知从细胞结构上无关的多种两亲性化合物中排出。 PGP在多药耐药性癌细胞中均表达，以及许多正常组织，例如肝脏，肾脏，小肠，结肠和大脑的组织，这表明PGP的生理作用是针对异种生物和内源代谢物的保护机制。接触到单一细胞毒性药物（例如VINCA生物碱，蒽环类药物，紫菜素或放线肌蛋白D），细胞可以过表达PGP并表现出MDR表型。 PGP过表达不仅是由化合物引起的，而且还由X射线和紫外线光照射或热休克引起的身体应力引起。目前大约有50％的销售药物被确定为PGP底物和/或抑制剂。 PGP可以通过为控制吸收，分布，代谢，消除和/或毒性的过程做出贡献（ADMET）来影响药物的药代动力学。此外，PGP与涉及共同管理PGP底物和调节剂的药物相互作用有关。例如，肠道PGP介导了包括紫杉醇在内的药物的实质性直接直接旋转。 ABCB1不是低聚物，而是与二聚体原核ABC转运蛋白（例如MSBA）同源的，该转运蛋白已由KU波段鹿成功地在ACERT上进行了研究。