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Current Medicinal Chemistry 2010P-glycoprotein (P-gp) is an ATP-driven transmembrane transporter capable of effluxing a wide variety of structurally diverse and functionally unrelated hydrophobic... (Review)
Review
P-glycoprotein (P-gp) is an ATP-driven transmembrane transporter capable of effluxing a wide variety of structurally diverse and functionally unrelated hydrophobic compounds out of the cell. Multidrug resistance (MDR), often associated with the over-expression of P-gp, has been implicated as a major obstacle to effective chemotherapy for cancer, parasitic diseases, AIDS, and other diseases. Drug efflux mediated by P-gp is also involved in decreasing the oral bioavailability of drugs by limiting intestinal absorption. Our appreciation of the structural and functional aspects of P-gp has definitely improved in recent years, benefiting from the deciphering of the structure of some bacterial transporters that paved the way for construction of homology models for more complex transporters. Here, we will review the recent advances in the studies of the structure and functional characteristics of P-gp with the hopes of facilitating rational drug design in developing novel potent MDR modulators.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Drug Design; Drug Resistance, Multiple; Humans; Models, Molecular; Neurodegenerative Diseases; Polymorphism, Genetic; Substrate Specificity
PubMed: 20088754
DOI: 10.2174/092986710790514507 -
SLAS Discovery : Advancing Life... Jan 2021In drug discovery it is essential that one of the parameters tested for any new chemical entity is its affinity for human efflux systems, most notably P-glycoprotein...
In drug discovery it is essential that one of the parameters tested for any new chemical entity is its affinity for human efflux systems, most notably P-glycoprotein (P-gp). These efflux systems affect not only rates of oral absorption but also rates of excretion through the liver, blood-brain barrier, and accumulation in potential target cells that upregulate efflux systems. Current methods to determine drugs' P-gp transport potential include in vitro bidirectional transport studies, and the two most common cell lines used are Caco2 and MDR1-transfected MDCK models. Caco2 cells are human but slow growing and require more than 3 weeks to mature, while MDCK cells are canine, but when transfected with human P-gp become a rapid model of P-gp affinity. Our laboratory has generated a Caco2 subclone called CLEFF4 that is fully human, yet now approaches the rapid nature of the MDCK model. No special medium is required. We have shown, in as little as 5 days postseeding, high transepithelial electrical resistance values of more than 1000 Ω·cm plus P-gp expression more than threefold higher than that of 21-day-old cells. Currently tested drugs included rhodamine 123 (Rh123), vinblastine, and doxorubicin, and all drugs exhibited P-gp-mediated efflux that was inhibited by PSC833. By day 6, bidirectional transport of Rh123 was as potent as that of mature Caco2 cells, for use in comparative P-gp affinity studies. We now have a human P-gp model that is rapid and works without any need for special accelerating medium. We believe this could be a welcome addition to the testing regime of new chemical entities.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Assay; Biological Transport; Cell Culture Techniques; Cell Line; Drug Discovery; Humans; Ion Channel Gating
PubMed: 32706283
DOI: 10.1177/2472555220942758 -
Pharmacological Reports : PR 2012This review provides an overview of the knowledge on P-glycoprotein (P-gp) and its role as a membrane transporter in drug resistance in epilepsy and drug interactions.... (Review)
Review
This review provides an overview of the knowledge on P-glycoprotein (P-gp) and its role as a membrane transporter in drug resistance in epilepsy and drug interactions. Overexpression of P-gp, encoded by the ABCB1 gene, is involved in resistance to antiepileptic drugs (AEDs), limits gastrointestinal absorption and brain access of AEDs. Although several association studies on ABCB1 gene with drug disposition and disease susceptibility are completed to date, the data remain unclear and incongruous. Although the literature describes other multidrug resistance transporters, P-gp is the main extensively studied drug efflux transporter in epilepsy.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Anticonvulsants; Drug Resistance; Humans; Pharmacogenetics
PubMed: 23238460
DOI: 10.1016/s1734-1140(12)70900-3 -
Pharmacotherapy Jul 2001P-glycoprotein (P-gp) is a cell membrane-associated protein that transports a variety of drug substrates. Although P-gp has been studied extensively as a mediator of... (Review)
Review
P-glycoprotein (P-gp) is a cell membrane-associated protein that transports a variety of drug substrates. Although P-gp has been studied extensively as a mediator of multidrug resistance in cancer, only recently has the role of P-gp expressed in normal tissues as a determinant of drug pharmacokinetics and pharmacodynamics been examined. P-glycoprotein is present in organ systems that influence drug absorption (intestine), distribution to site of action (central nervous system and leukocytes), and elimination (liver and kidney), as well as several other tissues. Many marketed drugs inhibit P-gp function, and several compounds are under development as P-gp inhibitors. Similarly, numerous drugs can induce P-gp expression. While P-gp induction does not have a therapeutic role, P-gp inhibition is an attractive therapeutic approach to reverse multidrug resistance. Clinicians should recognize that P-gp induction or inhibition may have a substantial effect on the pharmacokinetics and pharmacodynamics of concomitantly administered drugs that are substrates for this transporter.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Central Nervous System; Drug Interactions; Drug Resistance, Multiple; Humans; Kidney; Liver
PubMed: 11444575
DOI: 10.1592/phco.21.9.778.34558 -
Journal of Bioenergetics and... Dec 2005Human P-glycoprotein (ABCB1) is a primary multidrug transporter located in plasma membranes, that utilizes the energy of ATP hydrolysis to pump toxic xenobiotics out of... (Review)
Review
Human P-glycoprotein (ABCB1) is a primary multidrug transporter located in plasma membranes, that utilizes the energy of ATP hydrolysis to pump toxic xenobiotics out of cells. P-glycoprotein employs a most unusual molecular mechanism to perform this drug transport function. Here we review our work to elucidate the molecular mechanism of drug transport by P-glycoprotein. High level heterologous expression of human P-glycoprotein, in the yeast Saccharomyces cerevisiae, has facilitated biophysical studies in purified proteoliposome preparations. Development of novel spin-labeled transport substrates has allowed for quantitative and rigorous measurements of drug transport in real time by EPR spectroscopy. We have developed a new drug transport model of P-glycoprotein from the results of mutagenic, quantitative thermodynamic and kinetic studies. This model satisfactorily accounts for most of the unusual kinetic, coupling, and physiological features of P-glycoprotein. Additionally, an atomic detail structural model of P-glycoprotein has been devised to place our results within a proper structural context.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Electron Spin Resonance Spectroscopy; Humans; Kinetics; Models, Chemical; Thermodynamics
PubMed: 16691488
DOI: 10.1007/s10863-005-9497-5 -
Seminars in Cancer Biology Jun 1997We review how P-glycoprotein recognizes a wide variety of compounds and how it carries its substrates across membranes. Amino acid substitutions that affect the... (Review)
Review
We review how P-glycoprotein recognizes a wide variety of compounds and how it carries its substrates across membranes. Amino acid substitutions that affect the substrate specificity of P-glycoprotein have been found scattered throughout the molecule. In particular, some amino acid residues in the putative transmembrane domain (TM) 1 together with TM5-6 and TM11-12 may help to govern substrate specificity. The features that substrates for P-glycoprotein share are also discussed. The amphipathy of a substrate may decide whether the substrate can be intercalated into the lipid bilayer of the membrane. In addition, only certain molecular volumes and tertiary structures may make it possible for the substrate to fit into the substrate-binding site(s) of P-glycoprotein.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; DNA Mutational Analysis; Humans; Recombinant Fusion Proteins; Structure-Activity Relationship; Substrate Specificity
PubMed: 9441945
DOI: 10.1006/scbi.1997.0066 -
Biochimica Et Biophysica Acta Oct 1996
Review
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Clinical Trials as Topic; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans
PubMed: 8876632
DOI: 10.1016/0304-419x(96)00022-4 -
Cancer Metastasis Reviews Jun 1994P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been... (Review)
Review
P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been widely studied. Recent investigations have begun to focus on the relationship between Pgp detection in tumors and treatment outcome. In several types of tumors, detection of Pgp correlates with poor response to chemotherapy and shorter survival. P-glycoprotein over-expression often occurs upon relapse from chemotherapy but may also occur at the time of diagnosis. Studies of experimental rat liver carcinogenesis have shown that Pgp expression increases in late stages of carcinogenesis, suggesting that Pgp may be involved in tumor progression. While some of the Pgp isoforms are known to transport hydrophobic chemotherapeutic drugs out of tumor cells, the biologic effects of Pgp overexpression in tumor cells are not fully understood, because the spectrum of substrates for Pgp-mediated transport has not been determined. In the rat liver carcinoma model, strong expression of Pgp is associated with a highly vascular stroma, suggesting that Pgp in tumor cells may affect the connective tissue stroma. The regulation of Pgp appears to be complex, and little is known about how it is up-regulated during carcinogenesis. Further studies of the role of Pgp in malignancy may contribute to our understanding of molecular mechanisms which underlie tumor progression.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Drug Resistance, Multiple; Humans; Neoplasms; Neoplasms, Experimental
PubMed: 7923552
DOI: 10.1007/BF00689638 -
Journal of Pharmacological Sciences 2014In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood... (Review)
Review
In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Narcotics; Substrate Specificity; Transcription Factors
PubMed: 24989947
DOI: 10.1254/jphs.14r01cr -
The Journal of Membrane Biology Dec 1997Pgp is an atypical translocating ATPase, with low affinity for ATP and high constitutive ATPase activity. Pgp also has an unusually broad specificity for hydrophobic... (Review)
Review
Pgp is an atypical translocating ATPase, with low affinity for ATP and high constitutive ATPase activity. Pgp also has an unusually broad specificity for hydrophobic substrates, including many chemotherapeutic drugs. Transport studies in reconstituted systems indicate that drug transport requires ATP hydrolysis and is active, generating a drug concentration gradient. Binding of drugs and ATP to Pgp induces conformational changes in the protein, and the drug binding site is conformationally coupled to the NBDs. Evidence accumulated to date suggests that the transporter interacts directly with nonpolar substrates within the membrane environment, and may act as a drug flippase, moving drugs from the inner to the outer leaflet of the bilayer. Chemosensitizers that block the action of Pgp are proposed to act as alternative substrates, but their high rate of spontaneous flip-flop across the membrane results in futile cycling of the transporter.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Transport, Active; Drug Resistance, Multiple; Humans; Ion Transport
PubMed: 9425600
DOI: 10.1007/s002329900305