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)

DMRP, an ABC transporter encoded by the dMRP/CG6214 gene, is the Drosophila melanogaster orthologue of the "long" human multidrug resistance-associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP6/ABCC6, and MRP7/ABCC10). In order to provide a detailed biochemical characterisation we expressed DMRP in Sf9 insect cell membranes. We demonstrated DMRP as a functional orthologue of its human counterparts capable of transporting several human MRP substrates like beta-estradiol 17-beta-D-glucuronide, leukotriene C4, calcein, fluo3 and carboxydichlorofluorescein. Unexpectedly, we found DMRP to exhibit an extremely high turnover rate for the substrate transport as compared to its human orthologues. Furthermore, DMRP showed remarkably high basal ATPase activity (68-75 nmol Pi/mg membrane protein/min), which could be further stimulated by probenecid and the glutathione conjugate of N-ethylmaleimide. Surprisingly, this high level basal ATPase activity was inhibited by the transported substrates. We discussed this phenomenon in the light of a potential endogenous substrate (or activator) present in the Sf9 membrane.
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PMID:The high turnover Drosophila multidrug resistance-associated protein shares the biochemical features of its human orthologues. 1905 76

The non-small cell lung cancer (NSCLC) cells SK-LC6 and NCI-H23 were continuously exposed to vinorelbine (VNB), and the VNB-resistant clones, SK-LC6/VNB and H23/VNB were selected. Since SK-LS6/VNB and H23/VNB cells showed cross-resistance to certain anticancer drugs, such as paclitaxel and docetaxel, we examined the gene expression levels of drug efflux transporters of the ATP-binding cassette (ABC) family. We found that the gene expression of ABCB1/MDR1 and ABCC10/MRP7 in SK-LC6/VNB and H23/VNB cells was increased compared with that in SK-LS6 and NCI-H23 cells, whereas the expression of ABCC1/MRP1, ABCC2/MRP2, ABCC3/MRP3 and ABCG2/BCRP did not change among these cells. Treatment with ABCB1/MDR1 inhibitor verapamil and ABCC10/MRP7 inhibitor sulfin-pyrazone altered the sensitivity of SK-LC6/VNB cells to vinorelbine. To confirm the ABCC10/MRP7 activity, we transfected small interfering RNA against ABCC10/MRP7 to ABCC10/MRP7-expressing RERF-LC-AI cells resulting in the decrease of ABCC10/MRP7 expression concomitant with the alteration of VNB cytotoxicity. Moreover, we detected the expression of ABCC10/MRP7 in 12 of 17 NSCLC cells, whereas ABCB1/MDR1 was detected in only 3 of 17 NSCLC cells. These results indicate that ABCC10/MRP7 may confer VNB resistance in NSCLC.
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PMID:ABCC10/MRP7 is associated with vinorelbine resistance in non-small cell lung cancer. 1908 71

Efavirenz, an important component of human immunodeficiency virus 1 (HIV-1) therapy, causes substantial drug interactions as an inducer of cytochromes and the transporter ABCB1. So far its effect on the expression of other transporters is unknown. We therefore investigated the effect of long-term exposure of cells to efavirenz on expression of a large number of important drug transporters and on cell proliferation as a surrogate of intracellular availability. LS180 cells were used as a surrogate for the major site of drug interactions and Jurkat cells were used as a surrogate for the main target cells of HIV therapy. Cells were treated with efavirenz over 4 weeks and mRNA expression of drug transporters was repeatedly quantified. After 4 weeks, efavirenz significantly up-regulated the mRNA of ABCB1, ABCG2, ABCC2, ABCC3, ABCC5, and SLCO3A1 in LS180 cells and ABCG2, ABCC1, ABCC4, ABCC5, and SLCO2B1 in Jurkat cells. However these changes in transporter expression did not influence cell proliferation indicating that intracellular efavirenz concentrations were likely not altered. Efavirenz induces mRNA expression of several drug transporters critically modulating the kinetics of other drugs. While these expressional changes will most likely not influence the efficiency of efavirenz itself, they might change the effect of other co-administered drugs.
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PMID:Induction of multiple drug transporters by efavirenz. 1923 66

Arsenic trioxide has been used as a therapeutic agent for acute promyelocytic leukemia and recently for some solid tumors. Although arsenic trioxide has been shown to significantly inhibit the growth of solid tumor cells in vitro, clinical trials indicate that arsenic trioxide alone is pool active against non-hematologic malignant diseases. To understand the mechanisms of arsenic resistance in solid tumor cells, we established two arsenic-resistant solid tumor cell lines, HepG2/AS and SGC7901/AS, isolated from human liver cancer cell line HepG2 and human gastric cancer cell line SGC7901, respectively, by a series of stepwise selections via treatment with increasing concentrations of arsenic trioxide. Three ABC transporter proteins, ABCB1, ABCC1 and ABCC2, were expressed increasingly and differently in two arsenic-resistant cell lines. Further, tumor suppressor p53 was overexpressed in two arsenic-resistant cell lines, but the levels of p53 mediators MDM2 and gankyrin, which regulate the ubiquitination of p53, increased simultaneously. In addition, an increase in the phosphorylation of Rb at Ser795 in the two cell lines might also result from the presence of MDM2 and gankyrin, which suggest that the inactivation of p53 and Rb contribute to drug resistance. These two arsenic-resistant solid tumor cell lines, HepG2/AS and SGC7901/AS, may be useful for studying the mechanism of arsenic resistance in solid tumors and may provide a way to overcome it.
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PMID:The overexpression of multidrug resistance-associated proteins and gankyrin contribute to arsenic trioxide resistance in liver and gastric cancer cells. 1951 7

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

Because melanomas are intrinsically resistant to conventional radiotherapy and chemotherapy, many alternative treatment approaches have been developed such as biochemotherapy and immunotherapy. The most common cause of multidrug resistance (MDR) in human cancers is the expression and function of one or more ATP-binding cassette (ABC) transporters that efflux anticancer drugs from cells. Melanoma cells express a group of ABC transporters (such as ABCA9, ABCB1, ABCB5, ABCB8, ABCC1, ABCC2, and ABCD1) that may be associated with the resistance of melanoma cells to a broad range of anticancer drugs and/or of melanocytes to toxic melanin intermediates and metabolites. In this review, we propose a model (termed the ABC-M model) in which the intrinsic MDR of melanoma cells is at least in part because of the transporter systems that may also play a critical role in reducing the cytotoxicity of the melanogenic pathway in melanocytes. The ABC-M model suggests molecular strategies to reverse MDR function in the context of the melanogenic pathway, which could open therapeutic avenues towards the ultimate goal of circumventing clinical MDR in patients with melanoma.
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PMID:Involvement of ABC transporters in melanogenesis and the development of multidrug resistance of melanoma. 1972 28

Multi-drug resistance 1 (MDR1, ABCB1), also known as P-glycoprotein (P-gp), restricts intestinal uptake of many drugs, and contributes to cellular resistance to cancer chemotherapy. In this study, we examined the pharmacologic characteristics of HM30181, a newly developed MDR1 inhibitor, and tested its capacity to increase the oral bioavailability and efficacy of paclitaxel, an anti-cancer drug usually given by intravenous injection. In the ATPase assay using MDR1-enriched vesicles, HM30181 showed the highest potency (IC(50)=0.63nM) among several MDR1 inhibitors, including cycloporin A, XR9576, and GF120918, and effectively blocked transepithelial transport of paclitaxel in MDCK monolayers (IC(50)=35.4nM). The ATPase inhibitory activity of HM30181 was highly selective to MDR1. HM30181 did not inhibit MRP1 (ABCC1), MRP2 (ABCC2), and MRP3 (ABCC3), and partially inhibited BCRP (ABCG2) only at very high concentrations. Importantly, co-administration of HM30181 (10mg/kg) greatly increased oral bioavailability of paclitaxel from 3.4% to 41.3% in rats. Moreover, oral co-administration of paclitaxel and HM30181 showed a tumor-inhibitory strength equal or superior to that of intravenous paclitaxel in the xenograft model in nude mice. These results identify HM30181 as a highly selective and potent inhibitor of MDR1, which in combination with paclitaxel, may provide an orally effective anti-tumor regimen.
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PMID:Selective inhibition of MDR1 (ABCB1) by HM30181 increases oral bioavailability and therapeutic efficacy of paclitaxel. 1990 71

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

Simultaneous exposure of lab animals to toxic doses of the human carcinogen arsenic (As) and the essential trace element selenium (Se) results in a remarkable mutual detoxification. A likely basis for this is the in vivo formation and biliary excretion of seleno-bis(S-glutathionyl) arsinium ion [(GS)(2)AsSe](-); however, the transport protein responsible for the biliary efflux of [(GS)(2)AsSe](-) has not been identified. The multidrug resistance protein 2 (MRP2/ABCC2) is an adenosine triphosphate (ATP)-binding cassette transporter expressed at the canalicular membrane of hepatocytes. Rat Mrp2 is known to excrete the As glutathione (GSH/GS-) conjugates arsenic triglutathione [As(GS)(3)] and monomethyl arsenic diglutathione [CH(3)As(GS)(2)] into bile, and in vitro studies have established As(GS)(3) as a substrate for human MRP2. In the present study, membrane vesicles prepared from human embryonic kidney (HEK293T) cells transfected with human MRP2 were used to demonstrate that MRP2 transports [(GS)(2)AsSe](-). In addition, the characteristics of MRP2 transport of As(GS)(3) and [(GS)(2)AsSe](-) were investigated. As(GS)(3) and [(GS)(2)AsSe](-) are chemically labile and have the potential to dissociate. However, arsenite (As(III)) +/- selenite (Se(IV)) transport was not detected in the absence of GSH or in the presence of the non-reducing GSH analog, ophthalmic acid, suggesting that the conjugates are the transported forms. The apparent K(m) values for [(GS)(2)AsSe](-) and As(GS)(3) were 1.7 and 4.2 microM, respectively, signifying high relative affinities. Membrane vesicles prepared from human erythrocytes, which express the MRP2-related MRP1/ABCC1, MRP4/ABCC4 and MRP5/ABCC5, transported As(GS)(3) in an MRP1- and ATP-dependent manner but did not transport [(GS)(2)AsSe](-). These results have important implications for the Se-dependent and -independent disposition of As.
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PMID:Selenium-dependent and -independent transport of arsenic by the human multidrug resistance protein 2 (MRP2/ABCC2): implications for the mutual detoxification of arsenic and selenium. 2058 51


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