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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 P-糖蛋白(P-gp，ABCB1)属于三磷酸腺苷结合盒(ABC)转运蛋白超家族，是由多药耐药基因(MDR1)编码的哺乳动物细胞膜磷酸糖蛋白。Pgp在肿瘤对细胞毒性药物的耐药性中发挥作用，并已知从细胞中排出结构无关的各种两亲性化合物。Pgp不仅在多药耐药癌细胞中表达，而且在肝、肾、小肠、结肠和脑等正常组织中也有表达，提示Pgp的生理作用是一种对外来物质和内源性代谢物的保护机制。细胞暴露于一种细胞毒性药物，如长春花碱、蒽环类药物、紫杉类化合物或放线菌素D后，可过度表达Pgp并表现出多药耐药表型。Pgp的过度表达不仅受到化学物质的诱导，还受到X射线和紫外线照射或热休克引起的物理应激的影响。目前上市的药物中约有50%已被确定为PGP底物和/或抑制剂。PGP可通过参与控制吸收、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还参与药物与药物的相互作用，涉及共同给药的Pgp底物和调节剂。例如，肠道PGP调节包括紫杉醇在内的药物的大量直接跨上皮排泄。ABCB1不是寡聚体，而是与二聚体原核ABC转运蛋白如MSBA同源，后者已在ACERT上被Ku-band鹿成功研究。