Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of ABC (ATP-binding cassette)-type drug efflux pumps, such as ABCB1, ABCC1 and ABCG2 in cancer cells confers multi-drug resistance (MDR) and represents a major cause of treatment failures in cancer therapy. Furthermore, there is increasing evidence for the important contribution of ABC-transporters to bioavailability, distribution, elimination and blood-brain barrier permeation of drug candidates. This review presents an overview on the different computational methods and models pursued to predict ABC-transporter substrate properties of drug-like compounds. They range from linear discriminant analysis to pharmacophore modelling and machine learning algorithms. Many of these models show a satisfying performance within the study-specific, defined chemical space but general applicability for the whole drug-like chemical space still needs to be proven. First attempts aiming towards selectivity profiling for ligands of the two polyspecific transporters ABCB1 and ABCG2 is also discussed. This might pave the way for a pharmacological profiling of compound series with special focus on their ADMET (absorption, distribution, metabolism, excretion and toxicity) properties.
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PMID:In silico prediction of substrate properties for ABC-multidrug transporters. 1872 Nov 11

Expression of multidrug resistance ABC transporters has been suggested as a functional marker and chemoprotective element in early human progenitor cell types. In this study we examined the expression and function of the key multidrug-ABC transporters, ABCB1, ABCC1 and ABCG2 in two human embryonic stem (HuES) cell lines. We detected a high level ABCG2 expression in the undifferentiated HuES cells, while the expression of this protein significantly decreased during early cell differentiation. ABCG2 in HuES cells provided protection against mitoxantrone toxicity, with a drug-stimulated overexpression of the transporter. No significant expression of ABCB1/ABCC1 was found either in the undifferentiated or partially differentiated HuES cells. Examination of the ABCG2 mRNA in HuES cells indicated the use of selected promoter sites and a truncated 3' untranslated region, suggesting a functionally distinct regulation of this transporter in undifferentiated stem cells. The selective expression of the ABCG2 multidrug transporter indicates that ABCG2 can be applied as a marker for undifferentiated HuES cells. Moreover, protection of embryonic stem cells against xenobiotics and endobiotics may depend on ABCG2 expression and regulation.
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PMID:High level functional expression of the ABCG2 multidrug transporter in undifferentiated human embryonic stem cells. 1879 8

The present study aimed to elucidate the contribution of the intracellular binding of drugs to multidrug resistance. For this purpose, uptake of rhodamines was studied in cells whose mitochondria had been uncoupled with carbonyl cyanide m-chlorophenylhydrazone. Surprisingly, in a variety of drug-untreated cells, presumed to be sensitive to multidrug resistance-type drugs, rhodamines were excluded from entering the cells. Thus, the amount of rhodamine 123 taken up into parental untreated K562 cells was less than the amount bound to the cell exterior. Rhodamine uptake was prevented by an active efflux pump. The efflux was inhibited by 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) and MK571 and, to a lesser extent, by ATP depletion, indomethacin, probenecid and vanadate. All the inhibitors, apart from NBD-Cl, are known to modulate multidrug resistance-associated protein (MRP) 1. Because MRP1 was expressed in all the cell lines tested and the efflux of rhodamines in MRP1 over-expressing cells was abolished by NBD-Cl, it appears that rhodamines are excluded from these cells by MRP1. On the other hand, the uptake of rhodamines into cells respiring with their coupled mitochondria demonstrated diminished sensitivity to NBD-Cl and MK571. Thus, active pumping into the mitochondria allowed enhanced uptake into the cells, overcoming the innate resistance. The innate resistance provided by MRP1 to cells prevents rhodamine dyes, and possibly drugs such as doxorubicin, from achieving equilibration of their concentration in the cytoplasm with their concentration in the external medium. The protection provided to multidrug resistance cells by ABC transporters has to overcome competition by passive uptake of the drugs and binding/uptake of the drugs into intracellular targets.
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PMID:Competition between innate multidrug resistance and intracellular binding of rhodamine dyes. 1912 Apr 55

ABCG2 is best known as a multidrug transporter capable of conferring resistance to cancer cells. However, the protein is also inherently expressed in numerous barrier tissues and intriguingly within hematopoietic stem cells. Unlike its partners ABCB1 and ABCC1, there is considerably less information available on the molecular mechanism of ABCG2. The transporter has a distinct topology and is presumed to function as a homodimer. However, a number of biochemical studies have presented data to suggest that the protein adopts higher order oligomers. This review focuses on this controversial issue with particular reference to findings from low resolution structural data. In addition, a number of molecular models of ABCG2 based on high resolution structures of bacterial ABC transporters have recently become available and are critically assessed. ABCG2 is a structurally distinct member of the triumvirate of human multidrug transporters and continues to evade description of a unifying molecular mechanism.
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PMID:Purification and structural analyses of ABCG2. 1912 53

EGFR mutations have been correlated to responsiveness to treatment with tyrosine kinase inhibitors. These drugs are themselves substrates for ABC transporters. In the present work we describe the immunohistochemical profile of an archival sample from a male Brazilian patient with no Asian ancestry and never smoker, diagnosed with non-small cell lung cancer. This tumor was found to contain an in-frame hemi- or homozygous deletion, E746-A750 in exon 19 of the EGFR gene. Immunohistochemistry revealed a relatively weak staining for the ABC transporter subfamily ABCC1 and strongly for ABCB1. The cytoplasm stained positively for Bax and the nucleus stained for p53, but was negative for Bcl-2. Antibody against acetylated lysine revealed staining in both, cytoplasm and nucleus of tumor cells in contrast to normal cells which were essentially negative. The overall immunohistochemistry pattern obtained for this sample indicates that the del E746-A750 mutation may have down-regulated the expression of ABCC1. The results also suggest that the NSCLC analyzed displayed a transcriptionally active chromatin as judged by the results obtained with the anti-acetylated lysine antibody.
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PMID:Expression of ABC transporters, p53, Bax, Bcl-2 in an archival sample of non-small cell lung cancer bearing a deletion in the EGFR gene. 1936 Mar 19

FOLFOX is a cytostatic drug combination for adjuvant treatment of colorectal cancer (CRC) consisting of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. The mechanism of synergistic interaction of these drugs is poorly understood and little is known concerning the role of drug transporters and the impact of oxaliplatin metabolites oxalate and dichloro-diaminocyclohexane platinum. We therefore investigated the influence of FOLFOX components on drug transporter expression by quantitative real-time polymerase chain reaction and on the efficacy of each FOLFOX component by proliferation assay in the CRC model cell line LS180. Control experiments with transporter over-expressing cell lines were used to assess the significance of important transporters for the cytostatic activity of FOLFOX components. Moreover, we assessed the pharmacological contribution of the oxalato-ligand to the effect of oxaliplatin. FOLFOX components led to several alterations in expression of drug transporters. For instance, 5-FU significantly suppressed ATP7B and human organic cation transporter 2 and increased multidrug resistance-associated protein (MRP) 2 mRNA expression (5.8-fold). This was accompanied by a significant sensitisation to oxaliplatin. Over-expression of certain ABC-transporters (BCRP/ABCG2, MRP2/ABCC2 or MRP3/ABCC3) was demonstrated to be beneficial for the efficacy of oxaliplatin. The results obtained indicate that both down- and up-regulations of drug transporters could favour synergistic action of this drug combination. Moreover, oxaliplatin metabolite oxalate seems to positively modulate oxaliplatin's action as elucidated by median effect analysis. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.
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PMID:Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy. 1962 48

The myco-estrogene zearalenone (ZEA) is a worldwide cereal contaminant, implicated in reproductive disorders in animals and humans. Intestinal cells constitute a first barrier to mycotoxins exposure, since they express membrane ABC transporters that may affect the bioavailability of food xenobiotics. In this study, we investigated the mechanisms involved in the transepithelial transfer of ZEA and its major metabolites alpha- and beta-zearalenols (ZOLs), first using human intestinal Caco-2 cells. When exposed to ZEA, alpha-ZOL or beta-ZOL either in the apical (AP) or basolateral (BL) compartment, cells showed asymmetry in the AP-BL and BL-AP transfer of mycotoxins. Metabolic inhibitors increased ZEA, alpha-ZOL and beta-ZOL intracellular accumulation. Caco-2 cells apically exposed to ZEA produced metabolites (ZOLs and glucuronides) whose distribution between AP, BL and intracellular compartments was significantly modified by ABCCs inhibitor MK571. ABCB1-, ABCC1-, ABCC2 and ABCC3-transfected cells were used for studies of intracellular accumulation of ZEA, alpha-ZOL and beta-ZOL with or without specific inhibitors, and for competitive studies using fluorescent substrates. The results showed that ZEA, alpha-ZOL and beta-ZOL were substrates for ABCC2. ABCC1 was also involved in ZEA and alpha-ZOL transport, whereas ABCC3 only interacted with beta-ZOL. These specific interactions suggest a role for ABCC1-3 transport proteins in zearalenone exposure and its resulting risk for human health.
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PMID:ABCC1, ABCC2 and ABCC3 are implicated in the transepithelial transport of the myco-estrogen zearalenone and its major metabolites. 1964 55

In this study we examined gene expression of a series of ABC efflux transporters in various rainbow trout (Oncorhynchus mykiss) tissues. Based on their reported toxicological relevance, we have used quantitative real time PCR SYBR green quantification methodology, with combination of absolute and relative approach, to quantify RNA expression of eight ABC transporters from three different families: abcb1 and abcb11, abcc1-5 and abcg2. Level of mRNA transcripts was measured in seven tissues: liver, brain, gonads, kidney, gills, proximal intestine and distal intestine, and the obtained expression profiles were compared with data available for related mammalian tissues. Most of the analyzed genes showed similar gene expression pattern as the ones found in mammals, with some notable exceptions. E.g., gills were in our study characterized by extremely low expression of all analyzed ABC genes; and despite the pronounced role of ABCC1 (MRP1) in protection of mammalian cells from chemical toxins, we found low expression of this transporter in trout tissues. Taken together, our study offers the first thorough insight into distribution pattern of (eco)toxicologically relevant ABC transporters, serving as a necessary base for further studies directed to better understanding of physiological and/or protective role of ABC transporters in fish.
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PMID:Gene expression analysis of the ABC efflux transporters in rainbow trout (Oncorhynchus mykiss). 1988 95

ABC-type drug efflux pumps, e.g., ABCB1 (=P-glycoprotein, =MDR1), ABCC1 (=MRP1), and ABCG2 (=MXR, =BCRP), confer a multi-drug resistance (MDR) phenotype to cancer cells. Furthermore, the important contribution of ABC transporters for bioavailability, distribution, elimination, and blood-brain barrier permeation of drug candidates is increasingly recognized. This review presents an overview on the different computational methods and models pursued to predict ABC transporter substrate properties of drug-like compounds. They encompass ligand-based approaches ranging from 'simple rule'-based efforts to sophisticated machine learning methods. Many of these models show excellent performance for the data sets used. However, due to the complex nature of the applied methods, useful interpretation of the models that can be directly translated into chemical structures by the medicinal chemist is rather difficult. Additionally, very recent and promising attempts in the field of structure-based modeling of ABC transporters, which embody homology modeling as well as recently published X-ray structures of murine ABCB1, will be discussed.
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PMID:Predicting ligand interactions with ABC transporters in ADME. 1993 27

This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.
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PMID:Pharmacogenetics of membrane transporters: an update on current approaches. 1995 6


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