Mediate the effluxABCA1 and ABCG1Uptake and effluxInhibitorsSubstratesProteinsCholesterol from peripheralMultidrug ResistaMacrophagesMembraneIntracellularLipidMetabolismSoluteCellularProteinBCRPTissuesMechanismApolipoproteinABCB1OverexpressionDrugInhibitionSuperfamilyMacrophageSubstrateIntestinalGenes involvedAminoGeneticMoleculesSignificantlyAdditionallyOsmoticCellsResistanceCellInvolvesRoleHumanProcessesPromotesDifferencesStructures
Mediate the efflux2
- ATP-binding cassette transporters ABCA1 and ABCG1 primarily mediate the efflux of cholesterol from peripheral cells. (diabetesjournals.org)
- A number of mechanisms involved in the occurrence of MDR have been described, including the overexpression of one or more ATP binding cassette (ABC) transporter proteins that mediate the efflux of many clinically relevant drugs. (spandidos-publications.com)
ABCA1 and ABCG12
- LXRs also transcriptionally regulate the cholesterol efflux transporters ABCA1 and ABCG1, and deficiency of ABCA1 is associated with decreased body weight ( 18 ), while ABCG1 deficiency protects against diet-induced obesity ( 19 ). (diabetesjournals.org)
- In agreement with the reduced preβ-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients' plasma. (biomedcentral.com)
Uptake and efflux1
- Two types of transporters are identified in intestine i.e. uptake and efflux transporters. (omicsonline.org)
Inhibitors5
- Because BAAA is usually equally fluorescent compared to its turned-over carboxylate product, CSCs are identified based on their ability to retain the BAAA product relative to the unactivated probe using efflux pump inhibitors. (bioskinrevive.com)
- However, for most BBB transporters, it is still difficult to synthesize selective probes and inhibitors to enable specific evaluation of the transport activities of the target transporters, because of the effects of other transporters, including functionally unknown transporters, as well as binding to brain tissues. (aspetjournals.org)
- However, this method has not been used clinically due to the wide distribution of ABC transporters throughout the body, the potential toxicity of inhibitors, and unexpected drug-drug interactions [ 10 ] . (encyclopedia.pub)
- Dual inhibitors of P-gp and BCRP and inhibitors of Pdr5 were identified, and distinct structure-activity relationships for transporter inhibition were revealed. (th-koeln.de)
- BeWo cells were treated with 3H-lopinavir in the absence or presence of inhibitors of ATP- Binding Cassette transporters. (vcu.edu)
Substrates7
- The ATPase subunits utilize the energy of adenosine triphosphate (ATP) binding and hydrolysis to provide the energy needed for the translocation of substrates across membranes, either for uptake or for export of the substrate. (wikipedia.org)
- ABC transporters utilize the energy of ATP binding and hydrolysis to transport various substrates across cellular membranes. (wikipedia.org)
- The membrane-spanning region of the ABC transporter protects hydrophilic substrates from the lipids of the membrane bilayer thus providing a pathway across the cell membrane. (wikipedia.org)
- In many cases, transporters exhibit extremely high Gini coefficients, even when their supposed substrates might be expected to be available to all tissues, indicating a much higher degree of specialisation than is usually assumed. (biorxiv.org)
- Perland and Fredriksson, 2017 ) or the pharmaceutical drug substrates of these transporters, and one clue to this may be to understand their differential tissue distribution. (biorxiv.org)
- We previously reported that hepatobiliary transporter multidrug resistance-associated protein (MRP2/Mrp2) is considered to be the major cause of the interspecies differences detected by efflux of fluorescent substrates in isolated hepatocytes. (aspetjournals.org)
- These membrane transporters translocate a wide variety of substrates utilizing energy from ATP hydrolysis leading to decreased intracellular drug accumulation and impaired drug efficacy. (th-koeln.de)
Proteins10
- ABC transporters often consist of multiple subunits, one or two of which are transmembrane proteins and one or two of which are membrane-associated AAA ATPases. (wikipedia.org)
- ABC transporters are considered to be an ABC superfamily based on the similarities of the sequence and organization of their ATP-binding cassette (ABC) domains, even though the integral membrane proteins appear to have evolved independently several times, and thus comprise different protein families. (wikipedia.org)
- The third subgroup of ABC proteins do not function as transporters, but are rather involved in translation and DNA repair processes. (wikipedia.org)
- Pathogens use siderophores, such as Enterobactin, to scavenge iron that is in complex with high-affinity iron-binding proteins or erythrocytes. (wikipedia.org)
- Dr. Remaley's laboratory is now focused on how the ABCA1 transporter interacts with other intracellular proteins, as well as with extracellular cholesterol acceptor proteins, such as apoA-I, during the cholesterol efflux process. (nih.gov)
- However, because of the unknown binding affinity of antibody to MRP2/Mrp2 protein across species and lack of purified MRP2/Mrp2 proteins for calibration, the immunoblotting assay was excluded from the absolute quantification of MRP2/Mrp2 protein for multiple species. (aspetjournals.org)
- Multidrug resistance caused by the overexpression of ABC transporter proteins in cancer cells remains a major obstacle limiting chemotherapy efficacy. (spandidos-publications.com)
- It was previously reported that proadifen (SKF-525A), a well-known cytochrome P450 monooxygenase inhibitor, not only has anti-proliferative potential in some cancer cell lines, but it is also able to inhibit BCRP and MRP1 transporter proteins ( 8 ). (spandidos-publications.com)
- A structural genomics approach is used to determine to the structures of proteins belonging to other classes of ABC transporters. (rug.nl)
- The ATP-binding cassette (ABC) of active transporters comprises a group of proteins that which facilitate efflux of anticancer drugs from cancer cells. (lu.se)
Cholesterol from peripheral1
- APOA4 on prebeta and prebeta-b particles efflux cholesterol from peripheral tissues via ATP-binding cassette transporter A1 (ABCA1) (step 3). (jci.org)
Multidrug Resista2
- ATP-binding cassette (ABC) membrane-associated transporters, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein (MRP1) show significant expressions at the BBB, protecting the brain from potential harmful endogenous and exogenous substances [ 6 ] [ 7 ] . (encyclopedia.pub)
- Thus, three natural products and nine novel 3,4-dihydroisocoumarins were designed and analyzed regarding cytotoxicity induction and inhibition of human ABC transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) in a variety of human cancer cell lines as well as the yeast ABC transporter Pdr5 in Saccharomyces cerevisiae. (th-koeln.de)
Macrophages2
- Recent studies have demonstrated that ATP-binding cassette protein A1 (ABCA1) is highly regulated in macrophages and mediates the efflux of cholesterol and phospholipids to apolipoproteins, a process necessary for HDL formation. (jci.org)
- GLSP reduced the number of foam cells by improving ABCA1/G1-mediated cholesterol efflux in macrophages. (thno.org)
Membrane3
- We analyse two comprehensive transcriptome datasets from human tissues and human-derived cell lines in terms of the expression profiles of the SLC and ABC families of membrane transporters. (biorxiv.org)
- It has been reported that solute carrier (SLC) and the ATP-binding cassette (ABC) transporter super families are the major class of membrane transporters [ 14 , 17 ]. (omicsonline.org)
- The exact biological mechanism(s) by which the BBB limits drug exposure is not clear, but in addition to epithelial tight junctions, enhanced efflux of chemotherapeutic agents out of the CNS space by endothelial cell membrane transporters in brain blood vessels plays a primary role ( 2 ). (jcancer.org)
Intracellular5
- These transporters promote unidirectional cholesterol efflux to lipid-poor apolipoprotein A-I (apoA-I), apoE, or HDL particles, respectively, and are under the transcriptional control of liver X receptors (LXRs), master intracellular sensors that are activated in response to cholesterol biosynthetic intermediates and oxysterols ( 11 , 12 ). (diabetesjournals.org)
- MDR is often related to the expression of drug efflux transporters belonging to the ATP Binding Cassette (ABC) family, that pump drugs outside the cells limiting their intracellular accumulation and toxicity. (mdpi.com)
- Several compounds have been shown to inhibit the efflux activity of ABC transporters, thereby increasing intracellular drug accumulation and sensitising cancer cells to therapy. (spandidos-publications.com)
- Moreover, we revealed the ability of proadifen to increase the intracellular hypericin content in HT-29 cells most likely via the inhibition of BCRP and MRP1 transporters ( 8 ). (spandidos-publications.com)
- One of the ABC transporters that is studied in detail is the osmoregulatory ABC transporter OpuA (class D). Osmotic control of OpuA involves gating by intracellular ionic strength and is mediated by lipid-protein interactions. (rug.nl)
Lipid5
- The central helices of ApoA-I can promote ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux. (medlineplus.gov)
- Amino acid residues 220-231 of the wild-type ApoA-I are required for lipid efflux in vitro and high density lipoprotein formation in vivo. (medlineplus.gov)
- While LXR-deficient mice are leaner than littermate controls and are protected against diet-induced obesity, the mechanisms that control fat loss in these mice are still a matter of debate and could involve either reduced lipogenesis, enhanced lipid oxidation and lipolysis, or reduced cholesterol efflux pathways ( 14 ). (diabetesjournals.org)
- Mutation occurring in ATP binding cassette transporter 1 (ABC1) which enables exit of cholesterol from the cell with resultant decrease in the levels of lipid-rich HDL-lipoprotein in the circulation decrease. (researchsquare.com)
- ABC (ATP binding cassette) transporters catalyze the transport of a wide variety of molecules across lipid bilayers into or out of cells and organelles. (rug.nl)
Metabolism3
- The transport, metabolism and efflux of terfenadine and its metabolites were investigated in TC7 monolayers. (nih.gov)
- Ketoconazole increased the AP-BL transport terfenadine dramatically by inhibiting both terfenadine metabolism and Pgp efflux. (nih.gov)
- Xenobiotics and their metabolites are generally eliminated and detoxified by phase I and phase II enzymatic metabolism, by phase III transporter-mediated drug efflux to bile, or by both mechanisms. (aspetjournals.org)
Solute1
- Most of the uptake systems also have an extracytoplasmic receptor, a solute binding protein. (wikipedia.org)
Cellular3
- ABCA1 is expressed in many organs and is thought to mediate HDL maturation by facilitating the efflux of cellular phospholipids and cholesterol onto apolipoproteins. (jci.org)
- These factors include lopinavir plasma protein binding and uptake, cellular binding, and efflux of lopinavir in the placental trophoblast cells. (vcu.edu)
- The results suggested that interplay between cellular binding and ABC efflux transporters, in addition to simple diffusion, determines the extent of 3H-lopinavir distribution into BeWo cells. (vcu.edu)
Protein11
- Transporters are extremely vital in cell survival such that they function as protein systems that counteract any undesirable change occurring in the cell. (wikipedia.org)
- The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. (nih.gov)
- ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells. (nih.gov)
- In the second mechanism, gene products of erm (B) or erm (A) methylate the macrolide-binding site on 23S rRNA and stall bacterial protein synthesis. (cdc.gov)
- 71 Clusterin is a small heat shock glycoprotein overexpressed in most of the solid tumors, which promotes apoptosis by binding to various molecules such as BAX (BCL2-associated X protein) 72 and signal transducer and activator of transcription (STAT)−1. (oncologynurseadvisor.com)
- As we previously described, proadifen, a P450 monooxygenase inhibitor, might also be able to inhibit some ABC transporters, including breast cancer resistance protein (BCRP). (spandidos-publications.com)
- More than 40 ABC transporters have been identified so far, but just a few play a role in MDR, including the breast cancer resistance protein (BCRP/ABCG2). (spandidos-publications.com)
- Key drug efflux transporters operational in preserving the BBB are the P-glycoprotein (Pgp) transporter, which belongs to the ATP-binding cassette (ABC) transporter family, and the breast cancer resistance protein (BCRP) ABCG2 ( 4 , 5 ). (jcancer.org)
- The purpose of this study was to demonstrate experimentally that alterations of in vivo transporter function at the blood-brain barrier (BBB) in disease and during pharmacotherapy can be reconstructed from in vitro data based on our established pharmacoproteomic concept of reconstructing in vivo function by integrating intrinsic transport activity per transporter molecule and absolute protein expression level at the BBB. (aspetjournals.org)
- 3 The tandem CBS domain 4 , which is linked to the nucleotide binding protein, plays a pivotal role in the regulation. (rug.nl)
- They have a low placental transfer and are highly plasma protein bound. (vcu.edu)
BCRP2
- To characterize factors affecting milciclib pharmacokinetics, we investigated whether milciclib is a substrate of the multidrug effluX and uptake trans- porters ABCB1 (P-gp), ABCG2 (BCRP), and OATP1A/1B, and the drug-metabolizing enzyme CYP3A, using genetically-modified mouse models and Madin-Darby Canine Kidney (MDCK-II) cells. (srcinhibitors.com)
- The strongest inhibitor of P-gp and BCRP, which inhibited the transporters up to 80 to 90% compared to the respective positive controls, demonstrated the ability to reverse chemotherapy resistance in resistant cancer cell lines up to 5.6-fold. (th-koeln.de)
Tissues3
- The Gini index (coefficient) characterises inequalities of distributions, and is used in a novel way to describe the distribution of the expression of each transporter among the different tissues and cell lines. (biorxiv.org)
- Similar trends hold true for the expression profiles of transporters in different cell lines, suggesting that cell lines exhibit largely similar transport behaviour to that of tissues. (biorxiv.org)
- By contrast, the Gini coefficients for ABC transporters tend to be larger in cell lines than in tissues, implying that some kind of a selection process has taken place. (biorxiv.org)
Mechanism4
- High-resolution structures, biophysical and in silico studies have led to tremendous progress in understanding the mechanism of drug transport by these ABC transporters, and several promising therapies, including irradiation-based immune and thermal therapies, and nanomedicine have been used to overcome ABC transporter-mediated cancer chemoresistance. (nature.com)
- We suggest that current information regarding the structure, mechanism and regulation of ABC transporters should be used in clinical trials to improve the efficiency of chemotherapeutics for patients with cancer. (nature.com)
- A third, rare, mechanism is modification of the drug binding site on rRNA by mutation that is expressed as an M or a cMLS phenotype. (cdc.gov)
- A fourth mechanism suggests that cytotoxic drugs are removed from the source using efflux pumps, and the last mechanism is microtubule alterations that affect cytotoxic drug attachment to cancer cells. (oncologynurseadvisor.com)
Apolipoprotein1
- Chambenoit O, Hamon Y, Marguet D, Rigneault H, Rosseneu M, Chimini G. Specific docking of apolipoprotein A-I at the cell surface requires a functional ABCA1 transporter. (medlineplus.gov)
ABCB12
- Among the main mechanisms of this multidrug resistance is the overexpression of ATP-binding cassette (ABC) transporters that mediate drug efflux, and, specifically, ABCB1, ABCG2 and ABCC1 are known to cause cancer chemoresistance. (nature.com)
- In this Review, we highlight the progress achieved in the past 5 years on the three transporters, ABCB1, ABCG2 and ABCC1, that are known to be of clinical importance. (nature.com)
Overexpression1
- Various mechanisms are described to be involved in the development of MDR with overexpression of ATP-binding cassette (ABC) transporters reflecting the most extensively studied. (th-koeln.de)
Drug8
- ABC transporters are also involved in multiple drug resistance, and this is how some of them were first identified. (wikipedia.org)
- This ABC full-transporter is a member of the MRP subfamily which is involved in multi-drug resistance. (nih.gov)
- Fig. 3: Substrate-binding pockets of ATP-binding cassette transporters and the drug transport cycle. (nature.com)
- means that to understand drug distributions we must understand transporter distributions. (biorxiv.org)
- The first is active drug efflux mediated by an ATP-binding cassette transporter wherein mef (A) encodes the transmembrane domains and msr (D) encodes the ATP-binding domains ( 5 ). (cdc.gov)
- However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p-glycoprotein (Pgp) drug efflux pump. (jcancer.org)
- In addition, the presence of efflux transporters at the BBB has been recognized as a key element to poor drug penetration [ 6 ] [ 7 ] . (encyclopedia.pub)
- Studies showed that blocking ABC transporters may significantly improve drug penetrations across the BBB. (encyclopedia.pub)
Inhibition3
- Inhibition studies indicated that the efflux was mediated by Pgp. (nih.gov)
- One treatment strategy might be inhibition of transporter-mediated efflux by small molecules. (th-koeln.de)
- Molecular docking of the test compounds to P-gp revealed that differences in inhibition capacity were based on different binding affinities to the transporter. (th-koeln.de)
Superfamily1
- The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. (wikipedia.org)
Macrophage1
- Furthermore, we determined the major components of GLSP triterpenes, including Ganoderic acid A, Ganoderic acid B, Ganoderic acid C6, Ganoderic acid G, and Ganodermanontriol, and found that these triterpenes promoted ABCA1/G1-mediated cholesterol efflux and inhibited inflammation in macrophage, and inactivated RUNX2-mediated osteogenesis in VSMC. (thno.org)
Substrate4
- We address the molecular basis of their broad substrate specificity gleaned from structural information and discuss novel approaches to block the function of ABC transporters. (nature.com)
- Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. (jcancer.org)
- D. & E. Uptake systems with two or four covalently linked substrate-binding domains (SBDs). (rug.nl)
- Heide van der T., and Poolman, B. (2002) ABC transporters: one, two or four extracytoplasmic substrate-binding sites? (rug.nl)
Intestinal1
- Intestinal transporters play important role in drug's absorption and in turn its oral bioavailability . (omicsonline.org)
Genes involved2
- In particular, with some exceptions such as olfactory receptors and genes involved in keratin production, transporter genes are significantly more heterogeneously expressed than are most non-transporter genes. (biorxiv.org)
- In rodent brain, chronological aging, particularly before perimenopause, was associated with an up-regulation of genes involved in cholesterol synthesis, efflux, and export. (gremjournal.com)
Amino1
- Furthermore, genetic modification of ABC transporters by CRISPR-Cas9 and approaches to re-engineer amino acid sequences to change the direction of transport from efflux to import are briefly discussed. (nature.com)
Genetic2
- Genetic variation in the ATP binding cassette transporter ABCC10 is associated with neutropenia for docetaxel in Japanese lung cancer patients cohort. (nih.gov)
- Tangier disease, a rare genetic disorder characterized decades ago by Dr. Donald S. Frederickson at the NIH, is defective in the ABCA1 transporter and provided an early clue to the importance of the reverse cholesterol transport pathway. (nih.gov)
Molecules1
- It expresses multiple functional molecules, including transporters and receptors, and serves to control the traffic of a variety of molecules in and out of the CNS. (aspetjournals.org)
Significantly1
Additionally1
- Additionally, lopinavir binding to AAG and HSA was not sensitive to ritonavir within the range of therapeutic concentrations. (vcu.edu)
Osmotic1
- For instance, a potential lethal increase in osmotic strength is counterbalanced by activation of osmosensing ABC transporters that mediate uptake of solutes. (wikipedia.org)
Cells1
- Another focus of Dr. Remaley's work is on the main cholesterol efflux transporter from cells, namely the ATP-binding cassette transporter 1 (ABCA1). (nih.gov)
Resistance1
- However, ABC transporters are not the only cause of resistance. (mdpi.com)
Cell2
- Bacterial ABC transporters are essential in cell viability, virulence, and pathogenicity. (wikipedia.org)
- Next, we examined lopinavir uptake, binding and efflux using the BeWo human trophoblast cell culture model. (vcu.edu)
Involves2
- Cholesterol mobilization involves adipose tissue ATP-binding cassette transporter A1 (ABCA1), which has recently been shown to contribute to HDL biogenesis in vivo ( 9 , 10 ). (diabetesjournals.org)
- 3H lopinavir uptake was not sensitive to verapamil, bromosulfophthalein, taurocholate or to reduced temperature suggesting uptake involves diffusion rather than Organic Anion Transporting Polypeptide transporters. (vcu.edu)
Role2
- Revisiting the role of ABC transporters in multidrug-resistant cancer. (nature.com)
- However, the interpretation of this phenotype can be confounded by the fact that apoE plays a dual role promoting cholesterol efflux and mediating lipoprotein clearance ( 15 - 17 ) similar to SR-BI ( 5 , 6 , 11 ). (diabetesjournals.org)
Human1
- First, we determined the unbound fraction of lopinavir in cord blood and characterized the binding of lopinavir to α1-acid glycoprotein (AAG) and human serum albumin (HSA), and displacement by ritonavir. (vcu.edu)
Processes1
- Overall, these processes allow the regeneration of NAD + required for ATP production through glycolysis. (hindawi.com)
Promotes1
- By stimulating the expression of glucose transporters and glycolytic enzymes, HIF-1 promotes glycolysis to generate more pyruvate [ 5 ]. (hindawi.com)
Differences1
- Even though species differences in Mrp2-mediated biliary efflux have previously been reported, agreement on the degree of difference remains to be determined, because the absolute differences of transporters in these models remain unknown. (aspetjournals.org)
Structures1
- Fig. 2: Structures of three ATP-binding cassette transporters. (nature.com)