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

It is important to clarify the molecular characteristics of tumor cells showing multidrug resistance (MDR) and to identify the novel targets or biomarkers for chemotherapy. The aim of this study is to establish resistant HeLa sublines through exposure to SN-38, an active metabolite of irinotecan hydrochloride, and to investigate their molecular changes. HeLa cells were exposed to SN-38 at 1, 10, or 100 nM, and resistant clones were isolated and named HeLa/SN1, HeLa/SN10, and HeLa/SN100, respectively. Their cellular changes were examined based on growth inhibition assays, the function of ABCG2/BCRP, and a RT-PCR analysis of MDR-related protein. The sublines showed a decrease in sensitivity to not only SN-38 but also other chemotherapeutic agents as compared with HeLa cells. mRNA and protein levels of ABCG2/BCRP were increased, and the transport activity of ABCG2/BCRP was enhanced, in the resistant cells. In addition, the expression levels of ABCC1/MRP1, ABCC3/MRP3, and ABCC5/MRP5 were higher than in HeLa cells. The mRNA levels of GGT1 encoding a gamma-glutamyl transferase, but not GCS encoding a gamma-glutamyl cysteine synthetase, were also higher. Other factors examined, i.e., topoisomerase, SLCO1B1, and apoptosis-regulating factors, were comparable among the cells. The overexpression of ABCG2/BCRP was involved in the mechanism of resistance in SN-38-tolerant cells, and ABCC1/MRP1, ABCC3/MRP3, ABCC5/MRP5, and GGT1 may also have participated.
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PMID:Molecular changes to HeLa cells on continuous exposure to SN-38, an active metabolite of irinotecan hydrochloride. 1920 Oct 79

1. The multidrug resistance-associated proteins (MRPs) belong to the ATP-binding cassette superfamily (ABCC family) of transporters that are expressed differentially in the liver, kidney, intestine and blood-brain barrier. There are nine human MRPs that transport a structurally diverse array of endo- and xenobiotics as well as their conjugates. 2. Multidrug resistance-associated protein 1 can be distinguished from MRP2 and MRP3 by its higher affinity for leukotriene C(4). Unlike MRP1, MRP2 functions in the extrusion of endogenous organic anions, such as bilirubin glucuronide and certain anticancer agents. In addition to the transport of glutathione and glucuronate conjugates, MRP3 has the additional capability of mediating the transport of monoanionic bile acids. 3. Both MRP4 and MRP5 are able to mediate the transport of cyclic nucleotides and confer resistance to certain antiviral and anticancer nucleotide analogues. Hereditary deficiency of MRP6 results in pseudoxanthoma elasticum. In the body, MRP6 is involved in the transport of glutathione conjugates and the cyclic pentapeptide BQ123. 4. Various MRPs show considerable differences in tissue distribution, substrate specificity and proposed physiological function. These proteins play a role in drug disposition and excretion and thus are implicated in drug toxicity and drug interactions. Increased efflux of natural product anticancer drugs and other anticancer agents mediated by MRPs from cancer cells is associated with tumour resistance. 5. A better understanding of the function and regulating mechanisms of MRPs could help minimize and avoid drug toxicity and unfavourable drug-drug interactions, as well as help overcome drug resistance.
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PMID:Multidrug resistance-associated proteins and implications in drug development. 1956 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

We have hypothesized a suppressive mechanism against dietary docosahexaenoic acid (22:6n-3; DHA)-induced tissue lipid peroxidation, in which the degradation products, including their conjugates, are excreted into the urine by xenobiotic or organic anion transporters. In this study, we employed parent-strain Sprague-Dawley rats (SDRs), together with their mutant strain, Eisai hyperbilirubinuria rats (EHBRs). EHBRs are deficient in multidrug resistance-associated protein (MRP) 2, and show defective urinary excretion of numerous xenobiotics and organic anions. Both strains of rats were fed a diet containing DHA at 8.4% of total energy for 31 d. In the livers of the DHA-fed rats, the level of free malondialdehyde (MDA) + 4-hydroxy-2-alkenals (HAE) fell, and conversely glutathione S-transferase (GST) activity increased in MRP2-deficient EHBRs as compared to the SDRs, suggesting that the glutathione (GSH)-conjugation reaction for the aldehydes generated on DHA intake was accelerated in the MRP2-deficient EHBRs. Since the gene expression of liver MRP3 in the MRP2-deficient EHBRs was amplified to compensate for DHA intake, it is thought that the transport of MRP3 substrates into the bloodstream, rather than MRP2-mediated excretion of its substrates into the bile, was promoted. Indeed, excretion of mercapturic acid (acetylcysteine conjugates derived metabolically from the conjugate of each aldehyde with GSH) into the urine increased significantly in MRP2-deficient EHBRs fed DHA.
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PMID:Compensatory expression of MRP3 in the livers of MRP2-deficient EHBRs is promoted by DHA intake. 1989 18

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

Hepatic drug transporters are responsible for both hepatic uptake and the biliary excretion of drugs. Expression changes in hepatic drug transporter genes have been observed in various pathophysiological conditions. However, it has not been comprehensively investigated what factors substantially influence the mRNA levels of hepatic drug transporters. In this study, we quantified the mRNA expression of 17 drug transporters using noncancerous liver tissue samples and carried out stepwise multiple regression analysis to identify the factors affecting their expression from 18 clinical variables. For 17 drug transporters, the mRNA level of organic anion transporting polypeptide (OATP) 2B1 was highest, followed by that of organic cation transporter 1, organic anion transporter 2, OATP1B1, OATP1B3, multidrug resistance-associated protein (MRP) 6, and MRP3. Stepwise multiple regression analysis demonstrated MRP4 mRNA level to be predicted with the greatest accuracy among 17 drug transporters. Of clinical variables entered into the prediction model for MRP4, hepatitis C virus (HCV) infection and liver cirrhosis were crucial factors affecting MRP4 mRNA and protein levels. Furthermore, HCV-related cirrhosis influenced the mRNA levels of 8 drug transporters besides MRP4. These findings indicate that HCV-related cirrhosis is a crucial factor affecting the expression of hepatic drug transporters, especially MRP4.
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PMID:Hepatitis C virus-related cirrhosis is a major determinant of the expression levels of hepatic drug transporters. 2046 Aug 25

Caco-2 and T84 cells are intestinal epithelial model cells. Caco-2 cells are more commonly used in drug transport studies, whereas only a few studies have used T84 cells, and the two cell lines have not been compared. We cultured Caco-2 and T84 cells on plastic dishes or polycarbonate Transwell filters and compared the expression and function of ATP binding cassette (ABC) transporters, including multidrug resistance protein (MDR) 1 and multidrug resistance-associated protein (MRP) 2 and MRP3, in response to various compounds. Overall, the pattern of change in transporter mRNA expression in response to compounds was very similar regardless of culture conditions (plastic dish or polycarbonate filter) and cell line (Caco-2 or T84), and changes in MDR1 function was accompanied by expression changes. The cells cultured on Transwell filters were more sensitive to the tested compounds, regardless of the cell line. On comparing the two cell lines, the intrinsic function of MDR1 was stronger in Caco-2 cells, while sensitivity to the tested compounds was more prominent in T84 cells. These results suggest that Caco-2 cells are more suitable for identifying whether MDR1 mediates drug transport, while T84 cells are more useful for assessing the induction capacity of compounds.
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PMID:Comparison of the expression and function of ATP binding cassette transporters in Caco-2 and T84 cells on stimulation by selected endogenous compounds and xenobiotics. 2112 84

Macrophages represent major cellular targets of various drugs, especially antibiotics and anti-viral drugs. Factors that may govern intracellular accumulation of drugs in these cells, especially those related to activity of drug transporters, are consequently likely important to consider. The present study was therefore designed to extensively characterize expression of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in primary human macrophages generated from blood monocytes. Using quantitative polymerase chain reaction assays, these cells were found to exhibit very high or high levels of mRNA expression of concentrative nucleoside transporter (CNT) 3, equilibrative nucleoside transporter 3, monocarboxylate transporter (MCT) 1, MCT4, peptide/histidine transporter (PHT) 1, PHT2, organic anion transporting polypeptide transporter 2B1 and ABC pumps multidrug resistance protein (MRP) 1/ABCC1 and MRP3/ABCC3. By contrast, other transporters, including the efflux pump ABCB1/P-glycoprotein, were found at lower levels or were not expressed. Concomitantly, human macrophages displayed notable uptake of the MCT substrate lactate and of the CNT substrate uridine and also exhibited cellular efflux of the MRP substrate carboxy-2',7'-dichlorofluorescein. Such a functional expression of these transporters has likely to be considered with respect to cellular pharmacokinetics of drugs targeting macrophages.
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PMID:Drug transporter expression in human macrophages. 2121 Aug 49


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