This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.
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