Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance of cancer cells and pathogens is a serious clinical problem. A major factor contributing to drug resistance in cancer is the over-expression of P-glycoprotein, a plasma membrane ATP-binding cassette (ABC) drug efflux pump. Three-dimensional structural data with a resolution limit of approximately 8 A have been obtained from two-dimensional crystals of P-glycoprotein trapped in the nucleotide-bound state. Each of the two transmembrane domains of P-glycoprotein consists of six long alpha-helical segments. Five of the alpha-helices from each transmembrane domain are related by a pseudo-2-fold symmetry, whereas the sixth breaks the symmetry. The two alpha-helices positioned closest to the (pseudo-) symmetry axis at the center of the molecule appear to be kinked. A large loop of density at the extracellular surface of the transporter is likely to correspond to the glycosylated first extracellular loop, whereas two globular densities at the cytoplasmic side correspond to the hydrophilic, nucleotide-binding domains. This is the first three-dimensional structure for an intact eukaryotic ABC transporter. Comparison with the structures of two prokaryotic ABC transporters suggests significant differences in the packing of the transmembrane alpha-helices within this protein family.
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PMID:Three-dimensional structure of P-glycoprotein: the transmembrane regions adopt an asymmetric configuration in the nucleotide-bound state. 1548 7

Caveolin-1, the principal component of caveolae, is a 21-24 kDa integral membrane protein. The interaction of the caveolin-1 scaffolding domain with signaling molecules can functionally inhibit the activity of these signaling proteins. Little is known about how caveolin-1 influences the expression of P-glycoprotein (P-gp), an ABC transporter encoded by multi-drug resistance (MDR1) gene. To elucidate the possible mechanism between caveolin-1 and P-gp expression, in the present study, we overexpressed caveolin-1 in the Hs578T/Dox breast adenocarcinoma cells, a multidrug resistant line, and then selected single clone cells highly expressing caveolin-1 level. Both Western blot and confocal microscopy analyses showed that caveolin-1 was markedly overexpressed in the transfectants, while P-gp protein was almost abolished. Reverse transcription polymerase chain reaction also showed that the expression of P-gp mRNA was significantly suppressed in the transfectants. It was confirmed further by Northern blot analysis. Moreover, through measuring the changes of drug resistance and P-gp transport activity in the transfectants, we found that overexpression of caveolin-1 reversed drug resistance of transfectants and lowered their P-gp transport activity to the level of Hs578T/S. Taken together, our results indicate that such suppression of P-gp in the transfectants overexpressing caveolin-1 may occur at the transcriptional level.
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PMID:Suppression of P-glycoprotein gene expression in Hs578T/Dox by the overexpression of caveolin-1. 1549 65

One cause of multidrug resistance is the overexpression of P-glycoprotein, a 170 kDa plasma membrane ABC transporter, which functions as an ATP-driven efflux pump with broad specificity for hydrophobic drugs, peptides, and natural products. The protein appears to interact with its substrates within the membrane environment. Previous reports suggested the existence of at least two binding sites, possibly overlapping and displaying positively cooperative interactions, termed the H and R sites for their preference for Hoechst 33342 and rhodamine 123, respectively. In this work, we have used several fluorescence approaches to characterize the molecular interaction of purified P-glycoprotein (Pgp) with the dye LDS-751, which is proposed to bind to the R site. A 50-fold enhancement of LDS-751 fluorescence indicated that the protein binding site was located in a hydrophobic environment, with a polarity lower than that of chloroform. LDS-751 bound with sub-micromolar affinity (K(d) = 0.75 microM) and quenched P-glycoprotein intrinsic Trp fluorescence by 40%, suggesting that Trp emitters are probably located close to the drub-binding regions of the transporter and may interact directly with the dye. Using a FRET approach, we mapped the possible locations of the LDS-751 binding site relative to the NB domain active sites. The R site appeared to be positioned close to the membrane boundary of the cytoplasmic leaflet. The location of both H and R drug binding sites is in agreement with the idea that Pgp may operate as a drug flippase, moving substrates from the inner leaflet to the outer leaflet of the plasma membrane.
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PMID:Interaction of LDS-751 with P-glycoprotein and mapping of the location of the R drug binding site. 1564 90

Green tea extracts (GTE) might modulate ABC transporter gene expression or function. This may be relevant in the treatment of cancer or in influencing intestinal drug permeability. To gain more insight on the influence of a GTE on secretory transport proteins we investigated the influence of GTE and several green tea components on the mRNA expression level of P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) in human gastrointestinal epithelial LS-180 cells. Furthermore, the functional activity of MRP2, using glutathione methylfluorescein (GS-MF) or [3H]methotrexate (MTX) as substrate, was investigated in canine kidney cells stably overexpressing human MRP2 (MDCK-MRP2). GTE, at a concentration of 0.01 mg/mL, did not increase mRNA expression of P-gp or MRP2 in LS-180 cells. Functional assays in MDCK-MRP2 cells using GS-MF did not show any effect of 0.01 mg/mL GTE on MRP2 activity. In the same cell line the cellular accumulation of MTX (a specific substrate of MRP2) was significantly increased with the MRP-specific inhibitor MK-571 or with 1 mg/mL GTE, but not with 0.1 mg/mL. The green tea components (-)-epigallocatechin gallate, (-)-epigallocatechin, theanine, or caffeine, each in corresponding concentrations to the respective concentration of GTE, did not show any effect on MRP2 function. These data demonstrate that the mRNA expression patterns of P-gp and MRP2 in LS-180 cells are not altered by 0.01 mg/mL of GTE. However, MRP2 function was inhibited by 1 mg/mL GTE, whereas none of the green tea components tested were responsible for this effect.
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PMID:Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance-associated protein 2 functionality. 1572 21

ATP-binding cassette (ABC) transporters play a pivotal role in physiology and pathology. We identified and cloned two novel mRNA isoforms (ABCB 5alpha and ABCB 5beta) of the ABC transporter ABCB 5 in human melanoma cells. The deduced ABCB 5alpha protein appears to be an altered splice variant containing only a putative ABC, whereas the ABCB 5beta isoform shares approximately 70% similarity with ABCB1 (MDR1) and has a deduced topological arrangement similar to that of the whole carboxyl terminal half of the ABCB1 gene product, P-glycoprotein, including an intact ABC. Northern blot, real-time PCR, and conventional RT-PCR were used to verify the expression profiles of ABCB 5alpha/beta. We found that the melanomas included among the NCI-60 panel of cell lines preferentially expressed both ABCB 5alpha and ABCB 5beta. However, ABCB 5alpha/beta expression was undetectable in two amelanotic melanomas (M14 and LOX-IMVI). The expression profile of ABCB 5alpha/beta in all of the other melanomas of the panel was confirmed both by RT-PCR and by sequencing. Neither ABCB 5alpha nor ABCB 5beta expression was found in normal tissues such as liver, spleen, thymus, kidney, lung, colon, small intestines or placenta. ABCB 5alpha/beta mRNAs were also expressed in normal melanocytes and in retinal pigment epithelial cells, suggesting that ABCB 5alpha/beta expression is pigment cell-specific and might be involved in melanogenesis. Our findings indicate that expression of ABCB 5alpha/beta might possibly provide two novel molecular markers for differential diagnosis of melanomas and constitute potential molecular targets for therapy of melanomas.
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PMID:Principal expression of two mRNA isoforms (ABCB 5alpha and ABCB 5beta ) of the ATP-binding cassette transporter gene ABCB 5 in melanoma cells and melanocytes. 1576 Mar 39

P-glycoprotein (P-gp) is the most well-known ATP-binding cassette (ABC) transporter involved in unidirectional substrate translocation across the membrane lipid bilayer, thereby causing the typical multidrug resistance (MDR) phenotype expressed in many cancers. We observed that in human CEM acute lymphoblastic leukemia cells expressing various degrees of chemoresistance and where P-gp was the sole MDR-related ABC transporter detected, the amount of esterified cholesterol increased linearly with the level of resistance to vinblastine while the amounts of total and free cholesterol increased in a nonlinear way. Membrane cholesterol controlled the ATPase activity of P-gp in a linear manner, whereas the P-gp-induced daunomycin efflux decreased nonlinearly with the depletion of membrane cholesterol. All these elements suggest that cholesterol controls both the ATPase and the drug efflux activities of P-gp. In addition, in CEM cell lines that expressed increasing levels of elevated chemoresistance, the amount of P-gp increases to a plateau value of 40% of the total membrane proteins and remained unvaried while the amount of membrane cholesterol increased with the elevation of the MDR level, strongly suggesting that cholesterol may be directly involved in the typical MDR phenotype. Finally, we showed that the decreased daunomycin efflux by P-gp due to the partial depletion of membrane cholesterol was responsible for the efficient chemosensitization of resistant CEM cells, which could be totally reversed after cholesterol repletion.
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PMID:Control of P-glycoprotein activity by membrane cholesterol amounts and their relation to multidrug resistance in human CEM leukemia cells. 1576 80

In tumor cell lines, multidrug resistance is often associated with an ATP-dependent decrease in cellular drug accumulation which is attributed to the overexpression of certain ATP-binding cassette (ABC) transporter proteins. ABC proteins that confer drug resistance include (but are not limited to) P-glycoprotein (gene symbol ABCB1), the multidrug resistance protein 1 (MRP1, gene symbol ABCC1), MRP2 (gene symbol ABCC2), and the breast cancer resistance protein (BCRP, gene symbol ABCG2). In addition to their role in drug resistance, there is substantial evidence that these efflux pumps have overlapping functions in tissue defense. Collectively, these proteins are capable of transporting a vast and chemically diverse array of toxicants including bulky lipophilic cationic, anionic, and neutrally charged drugs and toxins as well as conjugated organic anions that encompass dietary and environmental carcinogens, pesticides, metals, metalloids, and lipid peroxidation products. P-glycoprotein, MRP1, MRP2, and BCRP/ABCG2 are expressed in tissues important for absorption (e.g., lung and gut) and metabolism and elimination (liver and kidney). In addition, these transporters have an important role in maintaining the barrier function of sanctuary site tissues (e.g., blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier or placenta). Thus, these ABC transporters are increasingly recognized for their ability to modulate the absorption, distribution, metabolism, excretion, and toxicity of xenobiotics. In this review, the role of these four ABC transporter proteins in protecting tissues from a variety of toxicants is discussed. Species variations in substrate specificity and tissue distribution of these transporters are also addressed since these properties have implications for in vivo models of toxicity used for drug discovery and development.
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PMID:Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. 1584 15

ATP binding cassette (ABC) multidrug transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2) confer resistance against anticancer drugs and can limit their oral availability, thus contributing to failure of chemotherapy. Like P-gp and BCRP, another ABC transporter, MRP2 (ABCC2), is found in apical membranes of pharmacologically important epithelial barriers and in a variety of tumors. MRP2 transports several anticancer drugs and might thus have a similar impact on chemotherapy as P-gp and BCRP. We here show that human MRP2 transduced into epithelial MDCKII cells efficiently transported the taxane anticancer drugs paclitaxel and docetaxel and that this transport could be substantially stimulated with the drug probenecid, a representative of a range of MRP2-stimulating drugs. Transport of 2 previously identified MRP2 substrates, etoposide and vinblastine, was likewise stimulated by probenecid. MRP2 further conferred substantial resistance against paclitaxel toxicity, and this resistance was 2.7-fold stimulated by probenecid. Our data indicate that MRP2 function might affect chemotherapy with taxanes, potentially influencing both tumor resistance and taxane pharmacokinetics. Moreover, coadministration of probenecid and other MRP2-stimulating drugs might lead to unforeseen drug-drug interactions by stimulating MRP2 function, potentially leading to suboptimal levels of taxanes and other anticancer drugs in plasma and tumor.
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PMID:MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. 1584 51

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.
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PMID:Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2. 1588 31

Breast cancer resistance protein (BCRP) is a newly identified ABC transporter, which plays an important role in drug disposition and represents an additional mechanism for the development of MDR. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be BCRP inhibitors. The objective of the present study was to elucidate the SAR and derive a QSAR model for flavonoid-BCRP interaction. The EC(50) values for increasing mitoxantrone accumulation in MCF-7 MX100 cells for 25 flavonoids, from five flavonoid subclasses, were determined in this study or obtained from our previous publication [Zhang S, Yang X, Morris ME. Combined effects of multiple flavonoids on breast cancer resistance protein (ABCG2)-mediated transport. Pharm Res 2004;21(7):1263-73], and ranged from 0.07+/-0.02 microM to 183+/-21.7 microM. We found that the presence of a 2,3-double bond in ring C, ring B attached at position 2, hydroxylation at position 5, lack of hydroxylation at position 3 and hydrophobic substitution at positions 6, 7, 8 or 4', are important structural properties important for potent flavonoid-BCRP interaction. These structural requirements are similar but not identical to those for potent flavonoid-NBD2 (P-glycoprotein) interaction, indicating that inhibition of BCRP by flavonoids may involve, in part, the binding of flavonoids with the NBD of BCRP. In addition, a QSAR model consisting three structural descriptors was constructed, and both internally and externally validated, suggesting the model could be used to quantitatively predict BCRP inhibition activity of flavonoids. These findings should be useful for predicting BCRP inhibition activity of other untested flavonoids and for guiding the synthesis of potent BCRP inhibitors for potential clinical application.
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PMID:Structure activity relationships and quantitative structure activity relationships for the flavonoid-mediated inhibition of breast cancer resistance protein. 1597 86


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