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PubMed2006

The functions and structure of ABC transporters: implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR).

Multidrug resistance (MDR) is a kind of acquired resistance of microorganisms and cancer cells to chemotherapic drugs that are characterized by different chemical structure and different mechanism of action. Classic MDR is the consequence of the over-expression of a variety of proteins that extrude the chemotherapic from the cell, lowering its concentration below the effective one. The ABC (ATP Binding Cassette) is a ubiquitous and important family of such transporter proteins. Members of this super family are present in mammals as well as in prokaryotic organisms and use ATP as the energy source to activate the extrusion process. P-glycoprotein (Pgp) and Multidrug Resistance Proteins (MRP1 and sister proteins) are the most important and widely studied members of ABC super family. Our knowledge about the structures and functions of transporter proteins has definitely improved in recent years, following the resolution of the structure of bacterial pumps which opened the way to the building of homology models for the more complex Pgp and MRP. It can be anticipated that these results will have a strong impact on the design of more potent and safer MDR reverters. A huge number of small molecules, many of natural origin, are able to reverse multidrug resistance by inhibiting the functions of Pgp, MRP1 and sister proteins and their action has been considered a possible way to reverse MDR. However, while a few compounds have reached clinical trials, none of them has, so far, been cleared for therapeutic use. Two main reasons are at the base of this difficulty: i) MDR is a complex phenomenon that may arise from several different biochemical mechanisms, with the consequence that inhibition of transporter proteins may be insufficient to reverse it; ii) the physiological role of Pgp and sister proteins requires more potent modulators with proper selectivity and pharmacokinetic in order to avoid unwanted side effects. This paper first reviews the most recent discoveries on the structures and functions of the ABC super family, in particular Pgp and MRP. Then, the medicinal chemistry of MDR reverters, in light of these findings, is discussed and the molecules that are presently in development are reviewed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

ABC transporters and sterol absorption.

Recent molecular studies, in particular investigations of subjects with monogenic disorders of lipoprotein metabolism and studies of induced-mutant mice, have increased the understanding of intestinal sterol absorption. Some of these genes encode adenosine triphosphate [ATP] binding cassette (ABC) transporters that transport dietary cholesterol from enterocytes back out to the intestinal lumen, thereby limiting the amount of cholesterol absorbed. ABC transporters also provide an effective barrier against the absorption of plant sterols, which are normally not absorbed in significant quantities by humans. This mechanism was clarified by the discovery that defects in two adjacent genes encoding ABC transporters are the molecular basis of sitosterolemia, a rare autosomal recessive disease in which plant sterols are absorbed due to failure of intestinal barrier to their absorption. Furthermore, recent experiments performed in induced-mutant mice have solidified the importance of these transporters in intestinal sterol absorption. Together with new developments in the biology of bile acids, sterol absorption is providing interesting directions for metabolism research. In addition to elucidating some of the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options to treat hypercholesterolemia and to help patients at risk of vascular disease reach ever-more stringent target levels.

ATP-Binding Cassette Transporters↗

PubMed2003

A test of the ABC model underlying rational emotive behavior therapy.

The ABC model underlying Ellis's Rational Emotive Behavior Therapy predicts that people who think more irrationally should respond to daily stressors or hassles differently than do people who think less irrationally. This study tested this aspect of the ABC model. 192 college students were administered the Survey of Personal Beliefs and the Hassles Scale to measure irrational thinking and daily hassles, respectively. Students who scored higher on overall irrational thinking reported a significantly higher frequency of hassles than did those who scored lower on overall irrational thinking, while students who scored higher on awfulizing and low frustration tolerance reported a significantly greater intensity of hassles than did those who scored lower on awfulizing and low frustration tolerance. This indicates support for the ABC model, especially Ellis's construct of irrational beliefs central to this model.

Adult↗

PubMed2004

Anger and the ABC model underlying Rational-Emotive Behavior Therapy.

The ABC model underlying Ellis's Rational-Emotive Behavior Therapy predicts that people who think more irrationally should display greater trait anger than do people who think less irrationally. This study tested this prediction regarding the ABC model. 186 college students were administered the Survey of Personal Beliefs and the State-Trait Anger Expression Inventory-Second Edition to measure irrational thinking and trait anger, respectively. Students who scored higher on Overall Irrational Thinking and Low Frustration Tolerance scored significantly higher on Trait Anger than did those who scored lower on Overall Irrational Thinking and Low Frustration Tolerance. This indicates support for the ABC model, especially Ellis's construct of irrational beliefs which is central to the model.

Adult↗

PubMed2004

Paraspinal musculature and skin temperature changes: comparing the Thermacare HeatWrap, the Johnson & Johnson Back Plaster, and the ABC Warme-Pflaster.

STUDY DESIGN: Prospective, randomized, crossover design. OBJECTIVES: To compare the effectiveness of the Johnson & Johnson Back Plaster, the ABC Warme-Pflaster, and the ThermaCare HeatWrap on skin and paraspinal muscle temperature. Also, to compare the subjects' heat perception for the 3 products. BACKGROUND: Heat therapy is a common treatment for low back pain and disability. There are a number of products on the market that are suggested to relieve low back pain by providing warmth to the back; however, their effectiveness for increasing tissue temperature compared with heat sensation has not been tested. METHODS AND MEASURES: To measure paraspinal muscle temperature, 1 thermocouple monofilament was inserted into the paraspinal muscle 2 cm from the skin surface at the L3 level using a 20-gauge 1.25-in (3.15-cm) sterile catheter. To measure skin interface temperature, 2 thermocouples were placed on the skin at distances of 5 cm and 7 cm from the insertion site. The Isothermex was used to record temperatures to the nearest 0.1 degrees C for 120 minutes. The subjects also rated heat perception using a 10-cm visual analog scale at 0, 30, 60, 90, and 120 minutes. Analysis of covariance models were used for statistical analysis. RESULTS: There was a significant product x time interaction (F14,231 = 3.77, P<.0001) at the intramuscular site, but there was not a significant product x time interaction (F14,231 = 1.03, P = .4228) at the skin site. Both the main effects for product (F2,33 = 41.59, P<.0001) and time (F3,51 = 19.02, P<.0001) were significant for the visual analog scale data. The ThermaCare HeatWrap produced significant increases in both skin and intramuscular temperatures with less heat sensation. The Johnson & Johnson Back Plaster and the ABC Warme-Pflaster increased temperature at the skin surface and provided the greatest heat sensations, but they did not provide intramuscular heat. CONCLUSIONS: The ThermaCare HeatWrap is more effective at increasing temperature at a 2-cm depth with less perceived heat compared to the Johnson & Johnson Back Plaster and the ABC Warme-Pflaster. The latter 2 products provide a sensation of heat but do not actually provide a muscle temperature change at a depth of 2 cm.

Adult↗

PubMed1990

An ABC-ELISA for malaria serology in the field.

An avidin biotin peroxidase complex enzyme-linked immunosorbent assay (ABC-ELISA) was examined for the diagnosis of malaria in a controlled area in Sudan Gezira. The titers of the ABC-ELISA coincided with those of the IFAT. The method was more sensitive than the ordinary ELISA as the final enzyme reaction was amplified through the use of the ABC system. This allowed the resulting color spots on the dried plate wells to be read clearly with the naked eye. This test can be carried out without using major electrical equipment.

Adult↗

PubMed1999

[The hematologic analyzer Vet ABC: evaluation of its use for dogs and cats].

The blood analyser Vet ABC was evaluated using the blood of dogs and cats. The correlation of results with those obtained with standard reference methods, reproducibility, and ease of operation were investigated. Good accuracy reproducibility were found in both species for leucocyte and erythrocyte counts, haematocrit, haemoglobin level, MCV, MCH, and MCHC. However, for some parameters new reference values will have to be established. The Vet ABC is not reliable for the measurement of platelets in the cat, and in the dog it does not give reproducible measurements of low numbers of platelets. In general, the Vet ABC is easy to use and does not need much maintenance.

Animals↗

PubMed2000

Cloning, characterization and tissue distribution of the rat ATP-binding cassette (ABC) transporter ABC2/ABCA2.

The ABC1 (ABCA) subfamily of the ATP-binding cassette (ABC) transporter superfamily has a structural feature that distinguishes it from other ABC transporters. Here we report the cloning, molecular characterization and tissue distribution of ABC2/ABCA2, which belongs to the ABC1 subfamily. Rat ABC2 is a protein of 2434 amino acids that has 44.5%, 40.0% and 40.8% identity with mouse ABC1/ABCA1, human ABC3/ABCA3 and human ABCR/ABCA4 respectively. Immunoblot analysis showed that proteins of 260 and 250 kDa were detected in COS-1 cells transfected with ABC2 having a haemagglutinin tag, while no band was detected in mock-transfected cells. After incubation with N-glycosidase F, the mobilities of the two proteins increased and a single band was detected, suggesting that ABC2 is a glycoprotein. Photoaffinity labelling with 8-azido-[alpha-(32)P]ATP confirmed that ATP binds to the ABC2 protein in the presence of Mg(2+). RNA blot analysis showed that ABC2 mRNA is most abundant in rat brain. Examination of brain by in situ hybridization determined that ABC2 is expressed at high levels in the white matter, indicating that it is expressed in the oligodendrocytes. ABC2, therefore, is a glycosylated ABC transporter protein, and may play an especially important role in the brain. In addition, the N-terminal 60-amino-acid sequence of the human ABC1, which was missing from previous reports, has been determined.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

The role of ring D in the antitumour antibiotic streptonigrin: metal complexation, DNA binding and topoisomerase inhibition by ABC ring analogues of streptonigrin.

interaction of 7-amino-2-(6'-carboxy-2'-pyridyl)-6-methoxy-5,8-quinolinedione, an ABC ring analogue of the antitumour antibiotic streptonigrin, with zinc(II), oligonucleotides and DNA in the presence of zinc(II), and on the relaxation of DNA by topoisomerase II, has been studied. This ligand contains the key functional groups present in streptonigrin required for biological activity, but lacks the phenolic ring D which confers optical activity on streptonigrin. Variable temperature NMR experiments showed that in the presence of zinc(II) triflate, the methyl ester of the ligand forms a mixture of 1:1 and 1:2 metal:ligand bipyridyl complexes, whose relative stabilities are temperature dependent. Titrations of the water-soluble ligand with zinc(II) nitrate at room temperature showed that the predominant species present in aqueous solution at physiological pH is the 1:1 bipyridyl complex. The interaction of the ligand with the hexanucleotides d(GCATGC)2 and d(ATGCAT)2 was studied by 1H- and 31P-NMR spectroscopy. In the presence of 1 equiv of zinc(II) nitrate and 1 equiv of the ligand, small changes in chemical shifts of the proton resonances associated with the purine resonances were detected consistent with a weak interaction of the zinc(II) complex of the ligand with the oligonucleotides, possibly via a groove binding mechanism. UV-VIS titrations showed a weak interaction of the ligand with calf thymus DNA and poly(dG-dC)2 in the presence of zinc(II) but negligible interaction with poly(dA-dT)2. Gel electrophoresis experiments showed that, in contrast to streptonigrin, the ligand did not inhibit the relaxation of plasmid DNA by human topoisomerase II. These results show that the interaction of the ABC ligand with zinc(II), oligonucleotides, DNA and topoisomerase II is different to streptonigrin and hence the design of biologically active ABC ring analogues of streptongrin that operate via different mechanisms should be possible.

Antibiotics, Antineoplastic↗

PubMed2000

Reconstruction of ABC Transporter Pathways of Archaea and Comparison of Their Genomes.

Reconstruction and comparison of metabolic pathway and regulatory network is an advanced task in genome function prediction. In this study, many bioinformatic tools were employed to reconstruct all ABC transporter pathways and predict their functional features of an archaeon, Pyrococcus abyssi, on genome scale. The comparison between ABC transporter pathways of P.abyssi and those of another archaeon, M.jannaschii, revealed that there was no peptide uptake ABC transporter system in M.jannaschii. This may result from their different metabolic types.

Journal Article↗

PubMed2003

Function of the ABC transporters, P-glycoprotein, multidrug resistance protein and breast cancer resistance protein, in minimal residual disease in acute myeloid leukemia.

BACKGROUND AND OBJECTIVES: Relapse is common in acute myeloid leukemia (AML) because of persistence of minimal residual disease (MRD). ABC-transporters P-glycoprotein (Pgp) and multidrug resistance protein (MRP), are thought to contribute to treatment failure, while it is unknown whether breast cancer resistance protein (BCRP) does so. However, whether up-regulation of pump activity or selection of subpopulations with higher pump activity occurs during chemotherapy is unclear. The aim of this study was to elucidate whether ABC-transporter function changes during the course of disease. DESIGN AND METHODS: MRD cells were identified using leukemia-associated phenotypes combined with a fluorescent probe assay with substrate/modulator: Syto16/ PSC833 (Pgp), calcein-AM/probenecid (MRP) and BODIPY-prazosin/Ko143 (BCRP); efflux profiles were directly compared with blasts at diagnosis and relapse from the same patient. RESULTS: At diagnosis BCRP activity was undetectable in AML blasts from 23/26 cases, while Pgp activity was present in 36/45 and MRP activity in 26/44 of the cases. Furthermore, no subpopulations of blasts with considerably higher drug efflux capacities were found. Overall, no consistent changes were observed at follow-up [during chemotherapy (n=20), MRD (n=37), relapse (n=26))] in forty-five patients, the mean activities (as percentages of values at diagnosis) were 97% (Pgp), 103% (MRP) and 102% (BCRP). INTERPRETATION AND CONCLUSIONS: Emergence of MRD is thus not accompanied by either upregulation of ABC-transporter function during or after chemotherapy or by selection of pre-existing highly resistant subpopulations. The prognostic value of Pgp and MRP is, therefore, likely related to drug efflux capacity homogeneously distributed in the whole blast population, while BCRP probably has a limited function in drug efflux-related resistance in AML.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1992

[Laboratory study and clinical evaluation of ABC-ELISA for detection of mycoplasma pneumoniae antigens].

Using anti-M. pneumoniae IgG obtained by immunizing rabbits with whole cell antigen of M. pneumoniae strain FH, we established an ABC-ELISA for detection of M. pneumoniae in simulated positive specimens, ABC-ELISA had a detection limit of 10(4) cfu/ml of specimen. There were no cross-reaction with 4 other species of human mycoplasmas and 12 common species of bacteria in respiratory tract. In 47 patients suspected of being M. pneumoniae infection, we compared the results of ABC-ELISA with the combined results from serodiagnostic methods and M. pneumoniae culture. The coincident rate between them was 80.9%.

Antigens, Bacterial↗

PubMed2004

ATP-binding cassette (ABC) transporters in human metabolism and diseases.

The ATP-binding cassette (ABC) superfamily of active transporters involves a large number of functionally diverse transmembrane proteins. They transport a variety of substrates including amino acids, lipids, inorganic ions, peptides, saccharides, metals, drugs, and proteins. The ABC transporters not only move a variety of substrates into and out of the cell, but also are also involved in intracellular compartmental transport. Energy derived from the hydrolysis of ATP is used to transport the substrate across the membrane against a concentration gradient. The typical ABC transporter consists of two transmembrane domains and two nucleotide-binding domains. Defects in 14 of these transporters cause 13 genetic diseases (cystic fibrosis, Stargardt disease, adrenoleukodystrophy, Tangier disease, etc.). Mutations in three genes affect lipid levels expressively. Mutations in ABCA1 cause severe HDL deficiency syndromes called Tangier disease and familial high-density lipoprotein deficiency, which are characterized by a severe deficiency or absence of high-density lipoprotein in the plasma. Two other ABCG transporters, ABCG5 and ABCG8, mutations of which cause sitosterolemia, have been identified. The affected individuals absorb and retain plant sterols, as well as shellfish sterols.

ATP-Binding Cassette Transporters↗

PubMed2006

[Plant ABC transporters--the family with tradition].

ATP binding cassette (ABC) transporters, which are found in all species, are known mainly for their ability to confer drug resistance. They have been thoroughly studied in mammals, where they became the center of interest for clinical reasons related to the resistance of tumor cells to chemotherapy treatment. Less is known about plant members of the ABC family, however, growing number of reports on their role in different physiological processes attract attention. The vacuolar ABC transporters in plants characterized to date are involved in the intracellular sequestration of cytotoxins (e.g. herbicides), as well as the products of endogenous metabolism like chlorophyll catabolites. Others localized within plasma membrane are active in the transport of secondary metabolites or phytohormones. Finally certain transporters are present in cell organelles and play a role in such processes as P oxidation. Here, we briefly introduce these proteins, and describe structural characteristic and physiological aspect of their activity in a plant cell.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

[Trial of replacement of ABC cement with the preparation Evicrol in fusing metal alloys used in prosthetic to the enamel].

The fusion strength was compared of the main metal alloys (Wiron 88, Wironit, Spal, Super Fluid) to the enamel by means of the ABC cement (Vivadent) and the preparation Evicrol (Spofa Dental). The obtained samples of metal alloys were subjected to abrasive blasting processing, defatted, and covered with the preparation "metal primer" from the ABC set, and fused to the pickled enamel with ABC cement and Evicrol preparation. The strength of the fusion was tested with the Instrom testing device. The fusion strength was greater in the case of Evicrol.

Dental Alloys↗

PubMed1990

The effects of chondroitinase ABC on the rabbit intervertebral disc. A roentgenographic and histologic study.

A series of intradiscal injections of chondroitinase ABC was performed in 31 young adult rabbits. Roentgenograms were taken immediately postinjection and were repeated at two, three, five, six, seven, or nine days after injection. All had roentgenographic evidence of disc space narrowing at all stages after the injection. Histologic evaluation of safranin-O fast green-stained sections indicated degradation of proteoglycans in the annulus fibrosus of chondroitinase ABC-injected discs. The cells of the chondroitinase ABC-injected discs, the end plates, and the growth-plate areas of adjacent vertebral bodies appeared unaffected.

Animals↗

PubMed1988

MHC class I and class I-like gene product expression by malignant T cells: relationships between CD1a, HLA-ABC and beta 2-microglobulin.

Beta 2-microglobulin (beta 2m) forms the invariant light chain of the MHC-encoded HLA-ABC and the non-MHC-encoded CD1 molecules. While HLA-ABC (MHC Class I) molecules are virtually ubiquitous in tissue distribution, CD1 determinants by contrast are more restricted. We have assessed, by indirect immunoenzymeassay, the relative membrane densities of these molecules on malignant thymic and post-thymic T cells. It was found that the T cells of mature post-thymic proliferations expressed significantly more beta 2m-associated protein, predominantly HLA-ABC in nature, than thymic-ALL blasts. This parallels the situation found in normal peripheral T cells and thymocytes. In contrast to post-thymic T cells, thymic-ALL blasts showed considerable case to case variation with respect to non-HLA-associated beta 2m and, of particular interest, not all of this excess beta 2m could be accounted for by CD1a. We therefore conclude that other beta 2m-containing molecules may be expressed on thymic-ALL blasts and possibly also on post-thymic leukaemic T cells. In addition, it was found that T cells from CD4+ cases of post-thymic proliferations expressed more beta 2m-associated determinants than other T cells, whether of either normal or malignant origin, and that certain post-thymic malignancies express significantly increased levels of beta 2m-associated protein relative to normal peripheral T-cells. This is in direct contrast to the situation seen in many solid malignancies.

Antigens, Differentiation↗

PubMed1985

ABC analysis of the relationship between pharmacy charges and DRGs.

DRGs and pharmacy charges were analyzed using the ABC analysis for a cross section of hospitals represented in the Blue Cross of Central Ohio (BCCO) region and for Riverside Methodist Hospital (RMH). A total of 43,969 patients were discharged from the 43 BCCO hospitals and 6,121 patients from RMH in the one-year study period. They were retrospectively assigned to 465 and 371 DRG categories, respectively. The ABC analysis of pharmacy charges and DRGs showed that 10 major diagnostic categories (MDCs) accounted for 80.4% and 80.1% of all pharmacy and i.v. charges for the BCCO hospitals and RMH, respectively. Hospital charges were found to be strongly related to pharmacy charges, and length of stay was found to be moderately related to pharmacy charges. In the absence of pharmacy cost data per DRG, the ABC analysis can be used to categorize DRGs on the basis of pharmacy charges. Before using pharmacy or hospital charges data per DRG for resource monitoring, hospital pharmacy directors should investigate the causes of high pharmacy charges for the high-cost DRGs and MDCs.

Blue Cross Blue Shield Insurance Plans↗