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Drug Metabolism Reviews Nov 2003The drug efflux transporter P-glycoprotein (P-gp) is known to confer multidrug resistance in cancer chemotherapy. The P-gp is highly expressed in many types of tumor... (Review)
Review
The drug efflux transporter P-glycoprotein (P-gp) is known to confer multidrug resistance in cancer chemotherapy. The P-gp is highly expressed in many types of tumor cells, as well as many normal tissues, including the apical surface of intestinal epithelial cells, and the luminal surface of capillary endothelial cells in the brain. Because of its expression and localization, it has been suggested that P-gp plays an important role in cancer chemotherapy, intestinal absorption, and brain uptake. This review addresses the significance of the role of P-gp in cancer chemotherapy, drug absorption, and brain uptake. Based on the clinical and animal studies with P-gp modulators, it has become apparent that the role of P-gp in multidrug resistance is far less important compared to other biological factors. Although P-gp is highly expressed in both intestinal epithelial cells and endothelial cells of brain capillaries and functions as an efflux transporter in both organs, the magnitude of P-gp's impact on intestinal absorption and brain uptake of drugs is quantitatively very different. From animal and clinical studies, it is evident that P-gp plays a very important role in CNS penetration of drugs, whereas the effect of P-gp on drug absorption is not as important as generally believed.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Humans; Neoplasms
PubMed: 14705869
DOI: 10.1081/dmr-120026871 -
Expert Opinion on Drug Metabolism &... Oct 2008P-glycoprotein is a blood-brain barrier efflux transporter that limits drug accumulation in the brain. (Review)
Review
BACKGROUND
P-glycoprotein is a blood-brain barrier efflux transporter that limits drug accumulation in the brain.
OBJECTIVE
To review recent in vivo and in vitro investigations that examined the influence of inflammation, infection and related clinical neuroinflammatory disorders on P-glycoprotein expression and activity in the brain.
METHODS
Critical overview of English-language studies.
RESULTS/CONCLUSIONS
Inflammation and infection produce dynamic changes in P-glycoprotein expression and activity in the blood-brain barrier. In vitro, blood-brain barrier P-glycoprotein activity is downregulated after short-term exposure to inflammatory mediators whereas its activity is upregulated following more prolonged exposure. In vivo studies in both humans and animals have linked CNS inflammation, peripheral inflammation and related clinical neuroinflammatory disorders with alterations in the expression and activity of blood-brain barrier P-glycoprotein. The direction and degree of change in P-glycoprotein activity depends on the in vivo or in vitro model examined, the cell type examined (e.g., endothelial or glial), the inflammatory mediator utilized, the anatomic site in which the inflammatory response was first generated, the time points chosen for observation and the substrates analyzed. Alterations in P-glycoprotein activity affect drug activity in the CNS and seem clinically important.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Brain; Gene Expression Regulation; Humans; Infections; Inflammation; Models, Biological; Nervous System Diseases; Time Factors
PubMed: 18798696
DOI: 10.1517/17425255.4.10.1245 -
Current Biology : CB Mar 1994The phenotype of mice homozygous for mutations of the mdr2 gene suggests that the mdr2 protein, which is closely related to the multidrug resistance P-glycoprotein, has... (Review)
Review
The phenotype of mice homozygous for mutations of the mdr2 gene suggests that the mdr2 protein, which is closely related to the multidrug resistance P-glycoprotein, has a role in phospholipid transport.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Resistance, Multiple; Homozygote; Mice; Mice, Mutant Strains; Models, Biological; Mutation; Phenotype; Phospholipids
PubMed: 7857397
DOI: 10.1016/s0960-9822(00)00059-2 -
Journal of Chemical Information and... Sep 2019The pumping of antitumor drugs by P-glycoprotein (P-gp) causes multidrug resistance (MDR) and consequent failure of chemotherapy. However, the understanding on the...
The pumping of antitumor drugs by P-glycoprotein (P-gp) causes multidrug resistance (MDR) and consequent failure of chemotherapy. However, the understanding on the molecular mechanism of P-gp for transporting substrates is still far from adequate. Herein, the transport of a typical antitumor drug, doxorubicin, by P-gp is investigated using targeted molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis. The MM-PBSA analysis identifies the driving forces for the transport of doxorubicin toward the extracellular space as electrostatic repulsions in the initial stage, which are contributed by positively charged residues (R148, K181, K189, K285, K291, K734, R789, K826, K934, and K1000) and then hydrophobic interactions provided by hydrophobic residues (L65, M69, F336, I340, F343, Y953, V982, F983, and M986). The contributions of these residues are further validated by targeted MD simulations, which shows blocked pumping after the mutation of these important residues to glycine. The MM-PBSA and minimum distance analyses of each residue during the transport reveal that the positively charged residues promote the transport of doxorubicin through long-range electrostatic repulsions and the hydrophobic residues provide a pathway through continuous hydrophobic interactions to maintain the transport. The results have thus provided molecular insights into the function of P-gp and would be beneficial in the design of potent P-gp inhibitors against MDR in the medication of cancers.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Doxorubicin; Humans; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Thermodynamics
PubMed: 31381334
DOI: 10.1021/acs.jcim.9b00429 -
Seminars in Cancer Biology Jun 1997In order to elucidate the mechanism by which the multidrug resistance P-glycoprotein extrudes cytotoxic drugs from the cell, and particularly the number and nature of... (Review)
Review
In order to elucidate the mechanism by which the multidrug resistance P-glycoprotein extrudes cytotoxic drugs from the cell, and particularly the number and nature of the drug binding site(s), knowledge of the structure of P-gp is essential. A considerable body of genetic and biochemical data has accrued which gives insights into P-gp structure and function. These data are critically reviewed, particularly in relation to the low resolution structure of P-gp which has recently been determined by electron microscopy. P-gp is one of the best characterised of the ABC transporters and these structure-function studies may have more general implications.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Humans; Protein Conformation; Protein Structure, Tertiary
PubMed: 9441943
DOI: 10.1006/scbi.1997.0067 -
Journal of Biomolecular Structure &... Mar 2019Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is...
Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is one of the main reasons for the multidrug resistance (MDR) of tumor cells. It has been confirmed that during the substrate transport process, P-gp experiences a large-scale structural rearrangement from the inward- to outward-facing states. However, the mechanism of how the nucleotide-binding domains (NBDs) control the transmembrane domains (TMDs) to open towards the periplasm in the outward-facing state has not yet been fully characterized. Herein, targeted molecular dynamics simulations were performed to explore the conformational rearrangement of human P-gp. The results show that the allosteric process proceeds in a coupled way, and first the transition is driven by the NBDs, and then transmitted to the cytoplasmic parts of TMDs, finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement, which mainly occurs in xy plane and ensures the formation of the correct ATP-binding pockets. The analyses on the interaction energies between the six structure segments (cICLs) from the TMDs and NBDs reveal that their subtle energy differences play an important role in causing the periplasmic parts of the transmembrane helices to separate from each other in the established directions and in appropriate amplitudes. This conclusion can explain the two experimental phenomena about human P-gp in some extent. These studies have provided a detailed exploration into human P-gp rearrangement process and given an energy insight into the TMD reorientation during P-gp transition.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Algorithms; Amino Acid Substitution; Drug Design; Humans; Models, Molecular; Molecular Dynamics Simulation; Mutation; Protein Binding; Protein Conformation; Structure-Activity Relationship
PubMed: 29620438
DOI: 10.1080/07391102.2018.1461133 -
Advanced Drug Delivery Reviews Mar 2002Efflux out of cells by P-glycoprotein (P-gp) represents a serious liability for pharmaceuticals, particularly for anti-cancer drugs. Consequently, identification of... (Review)
Review
Efflux out of cells by P-glycoprotein (P-gp) represents a serious liability for pharmaceuticals, particularly for anti-cancer drugs. Consequently, identification of compounds as potential substrates is important for understanding their bioavailability. Also, the development of agents which reverse this multi-drug resistance phenotype has received considerable attention. Assays for determining these activities are reviewed. Recent literature and studies into the structure-activity relationships (SAR) of the resulting data are discussed. Multiple binding sites and other complicating factors have prevented the development of a truly general, conclusive SAR either for substrate or inhibitory activities. Consequently, many models have tended to address only very general properties, such as lipophilicity and size. However, progress has been made in the last few years toward more specific SAR suggesting well-defined structural features responsible for both activities. The future of understanding the details of P-gp SAR lies in more specific assays that target specific binding sites and mechanisms of action.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Humans; Models, Molecular; Structure-Activity Relationship
PubMed: 11922950
DOI: 10.1016/s0169-409x(02)00006-6 -
Current Medicinal Chemistry.... Jan 2004A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance... (Review)
Review
A major problem in cancer treatment is the development of resistance to multiple chemotherapeutic agents in tumor cells. A major mechanism of this multidrug resistance (MDR) is overexpression of the MDR1 product P-glycoprotein, known to bind to and transport a wide variety of agents. This review concentrates on the progress made toward understanding the role of this protein in MDR, identifying and characterizing the drug binding sites of P-glycoprotein, and modulating MDR by P-glycoprotein-specific inhibitors. Since our initial discovery that P-glycoprotein binds to vinblastine photoaffinity analogs, many P-glycoprotein-specific photoaffinity analogs have been developed and used to identify the particular domains of P-glycoprotein capable of interacting with these analogs and other P-glycoprotein substrates. Furthermore, significant advances have been made in delineating the drug binding sites of this protein by studying mutant P-glycoprotein. Photoaffinity labeling experiments and the use of site-directed antibodies to several domains of this protein have allowed the localization of the general binding domains of some of the cytotoxic agents and MDR modulators on P-glycoprotein. Moreover, site-directed mutagenesis studies have identified the amino acids critical for the binding of some of these agents to P-glycoprotein. Furthermore, equilibrium binding assays using plasma membranes from MDR cells and radioactive drugs have aided our understanding of the modes of drug interactions with P-glycoprotein. Based on the available data, a topological model of P-glycoprotein and the approximate locations of its drug binding sites, as well as a proposed classification of multiple drug binding sites of this protein, is presented in this review.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Binding Sites; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Photoaffinity Labels; Structure-Activity Relationship
PubMed: 14754408
DOI: 10.2174/1568011043482142 -
Journal of Bioenergetics and... Feb 1995The multidrug resistance P-glycoprotein (P-gp) is an active drug transporter which can expel hydrophobic compounds from cells. Expression of P-gp has many effects on... (Comparative Study)
Comparative Study Review
The multidrug resistance P-glycoprotein (P-gp) is an active drug transporter which can expel hydrophobic compounds from cells. Expression of P-gp has many effects on cells and tissues and the physiological function, or functions, of P-gp are still unclear. Recently, expression of P-gp has been associated with altered activity of chloride channels which play a role in regulating cell volume of response to osmotic shock or nutrient uptake. The nature and physiological role of this association has been a subject of some debate. In this article, mechanisms by which P-gp might influence cell volume-activated chloride currents is discussed, and the potential physiological role of this regulation considered.
Topics: 3T3 Cells; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Animals; Biological Transport; Chloride Channels; Cystic Fibrosis Transmembrane Conductance Regulator; Gene Expression; Homeostasis; Humans; Membrane Proteins; Mice; Models, Structural; Recombinant Proteins; Transfection
PubMed: 7543087
DOI: 10.1007/BF02110332 -
Chinese Medical Journal Nov 2009A 65-kD mdr1 (multi-drug resistance protein 1, P-glycoprotein)-like protein has been suggested to be the regulatory protein to the chloride channel protein 3 (ClC-3)...
BACKGROUND
A 65-kD mdr1 (multi-drug resistance protein 1, P-glycoprotein)-like protein has been suggested to be the regulatory protein to the chloride channel protein 3 (ClC-3) mediating insulin granules acidification and release in mouse pancreatic beta cells. But the protein has not been deeply investigated. In this study, we identified existence of the 65-kda protein in rat islets and preliminarily explored its biological functions.
METHODS
Total RNAs of rat kidneys served as positive controls, and pancreas, islets and INS-1 cells were extracted for reverse-transcript PCR (RT-PCR), respectively. The cDNAs were run with specific primers selected from the mRNA of abcb1b encoding P-glycoprotein. All PCR products were visualized in agarose gel electrophoresis and sequenced. Homogenates of rat islets and INS-1 cells were applied to SDS-PAGE. P-glycoprotein was detected by a specific monoclonal antibody, C219. Biphasic insulin release was measured in static incubations of rat islets with radioimmunology assay.
RESULTS
Compared with positive control, expression of the P-glycoprotein mRNA segments were detected in the islets, INS-1 cells and pancreas. Sequence analysis confirmed that the PCR products were matched with mRNA of P-glycoprotein. A 65-kda protein was recognized by the antibody in the islets homogenate but not in that of INS-1 cells in Western-blotting. Instead, the homogenate of INS-1 cells contained a 160-kda protein recognized by the antibody. Insulin secretion of rat islets were stimulated by high glucose (16.7 mmol/L), and showed biphasic curve during 60-minute incubation. After co-incubation with cyclosporine A (CsA), specific inhibitor to P-glycoprotein, the second phase of insulin secretion was reduced significantly while the first phase was not influenced.
CONCLUSIONS
The 65-kda protein expressed in rat islets is most likely a mini-P-glycoprotein. It may play a key role regulating biphasic insulin release.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blotting, Western; Cell Line; Insulin; Insulin-Secreting Cells; Male; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 19951574
DOI: No ID Found