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)

The increased expression of drug transporters following cancer chemotherapy contributes to resistance. This may reflect transcriptional up-regulation and/or clonal selection. We quantified the expression of mRNA for ABCB1 (mdr1), ABCC1 (mrp1), ABCC2 (mrp2) and ABCC3 (mrp3) to evaluate the potential contribution of induction. ABCB1, ABCC1-3 mRNAs were quantified by real time RT-PCR and normalized to GAPDH. We used intestinal cells that express high pregnane X receptor (LS174T), low pregnane X receptor (Caco-2) and lung cells (A549) that express glucocorticoid receptor and low pregnane X receptor. Rifampin (10 microM) caused significant induction of ABCB1 (595+/-263%, p<0.05) in LS174T cells but induction was absent in Caco-2 or A549 cells. ABCC1 was not induced in any cell at 24, 48 and 72 h following rifampin treatment. In contrast, vincristine (10 nM and 100 nM), a ligand for ABCB1 and ABCC1-3 and a potential PXR/CAR ligand, induced ABCC2 and ABCC3 expression in LS174T cells at 48 h (372+/-87% and 303+/-42%, respectively, p<0.05). A similar induction of ABCC2 and ABCC3 genes was also seen with 10 nM VCR in A549 cells following 48 h treatment. In summary, there may be a significant contribution of transcriptional activation to multi-drug resistance. However, this is cell selective and is not necessarily dependent on PXR mediated effects.
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PMID:Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines. 1662 Jul 87

The purpose of this study was to quantify gene expression levels of the ATP-binding cassette (ABC) transporter A and C subfamilies ABCA1-A9, and ABCC1-6/Mrp1-6, C10/Mrp7 in mouse retinal vascular endothelial cells (RVEC) using a combination of a magnetic isolation method for mouse RVEC and real-time quantitative PCR analysis. The transcript level of endothelial cell markers, such as CD31, Tie-2, claudin-5, occludin, ABCB1a/mdr1a, and ABCG2, were more than 20-fold higher than those in the non-RVEC fraction, suggesting that RVEC in the RVEC fraction are concentrated at least 20-fold compared with those of the non-RVEC fraction. In the ABCA1 to A9 families, the transcript level of ABCA3 and A9 in the RVEC fraction was 1.2- and 32-fold higher than that in the non-RVEC fraction. Although ABCA3 was expressed in both the RVEC and non-RVEC fractions, A9 is predominantly expressed in the RVEC fraction. In the ABCC1 to C6 and C10 families, the transcript level of ABCC3, C4, and C6 in the RVEC fraction was 27-, 251-, and 242-fold higher, respectively, than that in the non-RVEC fraction, suggesting that ABCC3, C4, and C6 are predominantly expressed in the RVEC. In conclusion, ABCA3, ABCA9, ABCC3, ABCC4, and ABCC6 mRNAs are predominantly expressed at the inner blood-retina barrier (inner BRB) and appear to play a major role in the efflux transport of their substrates at the inner BRB.
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PMID:Gene expression profiles of ATP-binding cassette transporter A and C subfamilies in mouse retinal vascular endothelial cells. 1757 81

Nrf2, an NF-E2-related transcription factor, plays a critical role in transcriptional upregulation of many target genes, including those for metabolizing enzymes and transporters essential for cellular defense in response to oxidative and/or electrophilic stress. In the present study, we have studied the potential involvement of Nrf2 in induction of human ABC transporter genes under oxidative stress. We created a real-time PCR primer set to quantitatively investigate the induction of human ABC transporters by a redox-active compound tert-butylhydroquinone (tBHQ) in HepG2 cells. We found that mRNA levels of ABCC1, ABCC2, ABCC3, and ABCG2 were significantly elevated in dose- and time-dependent manners. Translocation of Nrf2 into the nuclei occurred concomitantly with the induction of ABCC1 and ABCC2 as well as both heavy and light chains of gamma-glutamylcysteine synthetase (gamma-GCSh and gamma-GCSI) during tBHQ treatments. To examine the potential involvement of Nrf2 in upregulation of the ABC transporters, we treated cells with siRNA to knockdown the expression of Nrf2. Under such Nrf2-knockdown conditions, tBHQ-induced mRNA levels of ABCC2 and ABCG2 were significantly suppressed as were mRNA levels of gamma-GCSh and gamma-GCSI. Interestingly, however, the elevated mRNA level of ABCC1 was little affected by Nrf2 siRNA treatment. We also addressed the involvement of Keap1, which is a negative regulator of Nrf2 by retrieving it in the cytoplasm. When HepG2 cells were treated with Keap1-specifc siRNA, a significant increase was observed in mRNA levels of ABCC1, ABCC2, and ABCG2 as well as gamma-GCSI, suggesting that induction of ABCC2 and ABCG2 by tBHQ is mediated by the Nrf2/Keap1 system, whereas the induction of ABCC1 may involve a Keap1-dependent but Nrf2-independent mechanism.
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PMID:Nrf2-dependent and -independent induction of ABC transporters ABCC1, ABCC2, and ABCG2 in HepG2 cells under oxidative stress. 1803 66

Xanthohumol (XN) and its related compounds were evaluated for their cytotoxicity against four different human cancer cell lines, A549 (lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), and HCT-15 (colon) using a sulforhodamine B assay. XN showed the most active cytotoxicity against the human cancer cell lines. Isoxanthohumol, 8-prenylnaringenin, and xanthohumol 4'-O-beta-D-glucopyranoside showed comparable cytotoxicity and (2S)-5-methoxy-8-prenylnaringenin 7-O-beta-D-glucopyranoside was the least cytotoxic compound. The anticancer properties of XN, the most active cytotoxic compound, were further investigated. XN showed an inhibitory effect on the activity of DNA topoisomerase I (topo I), which was measured from the relaxation of supercoiled DNA. The inhibition of topo I by XN might explain the cytotoxicity against the human cancer cell lines. Moreover, the expression of the drug efflux genes was investigated to predict the drug resistance. XN clearly decreased the mRNA levels of ABCB1 (MDR1), ABCC1 (MRP1), ABCC2 (MRP2), and ABCC3 (MRP3). These results suggest that XN has anticancer properties by inhibiting the topo I activity and it might be used in conjunction with other anticancer chemotherapeutic agents to reduce the drug resistance inhibiting the efflux drug transporters.
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PMID:Inhibition of topoisomerase I activity and efflux drug transporters' expression by xanthohumol. from hops. 1808 12

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.
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PMID:Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. 1869 Oct 54

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

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

While P-glycoprotein (PGP, ABCB1) is known to play an important role in drug exclusion at the blood brain barrier (BBB), less is known about the contribution of other members in the ATP-binding cassette (ABC) transporter family to BBB drug efflux, or whether these transporters are expressed differently in humans and in mammalian species of pharmacological interest. We used quantitative real-time PCR to determine mRNA expression levels for the majority of ABC family members in brain and in isolated brain microvessel endothelial capillary cells (BMEC) from human, rat, mouse, pig and cow. We confirmed BBB expression of several well-characterized ABC family members that are implicated in xenobiotic exclusion from the brain, including ABCB1 (PGP), ABCG2 (BCRP), ABCC1 (MRP1), ABCC4 (MRP4), and ABCC5 (MRP5). In addition, we detected high expression and enrichment in BMEC of several less well-characterized ABC transporters in one or more species, including ABCA2-4, ABCB4, ABCB6-8, ABCB10, ABCC3, ABCC6, ABCC10, and ABCE1. We also uncovered species differences in the expression of a number of transporters, including ABCG2 and ABCC4. This study identifies several additional ABC family members that may contribute to xenobiotic efflux at the human BBB, and compares the expression of a broad array of efflux transporters between human and four other species relevant to pharmacological research.
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PMID:Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. 1942 73


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