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)

Pseudoxanthoma elasticum (PXE; OMIM 177850 and 264800) is a rare heritable disorder of the connective tissue affecting the extracellular matrix of the skin, eyes, gastrointestinal system, and cardiovascular system. It has recently been found that mutations in the ABCC6 gene encoding the multidrug resistance-associated protein (MRP) 6 cause PXE. This study examined novel mutations in the ABCC6 gene in our cohort of 76 German PXE patients and 54 unaffected or not yet affected relatives with a view to expanding the known mutational spectrum of the gene. Mutational analysis was performed using denaturing high-performance liquid chromatography and direct sequencing. The mutational screening revealed a total of 22 different ABCC6 sequence variations. We identified seven novel and four previously described PXE-associated mutations as well as eight novel neutral ABCC6 sequence variants. The new PXE-associated mutations included five missense mutations, one single base pair deletion, and one larger out-of-frame deletion. We suspect that the novel missense mutations lead to an impaired function of MRP6. Both deletions are predicted to result in a dysfunctional MRP6 protein. The seven new ABCC6 mutations were not present in 200 alleles from healthy blood donors which served as a control cohort. Most of the PXE patients who were found to carry PXE-causing ABCC6 mutations were assumed to manifest the PXE phenotype because of a compound heterozygous genotype. However, a genotype-phenotype correlation could not be established for the detected ABCC6 mutations. In summary, our data give a further insight into the spectrum of ABCC6 mutations in PXE patients.
J Mol Med (Berl) 2005 Feb
PMID:New ABCC6 gene mutations in German pseudoxanthoma elasticum patients. 1572 64

Multidrug resistance protein (MRP)1/ABCC1 transports organic anionic conjugates and confers resistance to cytotoxic xenobiotics. In addition to two membrane spanning domains (MSDs) typical of most ATP-binding cassette (ABC) transporters, MRP1 has a third MSD (MSD0) of unknown function. Unlike some topologically similar ABCC proteins, removal of MSD0 has minimal effect on function, nor does it prevent MRP1 from trafficking to basolateral membranes in polarized cells. However, we find that independent of cell type, the truncated protein accumulates in early/recycling endosomes. Using a real-time internalization assay, we demonstrate that MSD0 is important for MRP1 retention in, or recycling to, the plasma membrane. We also show that MSD0 traffics independently to the cell surface and promotes membrane localization of the core-region of MRP1 when the two protein fragments are coexpressed. Finally, we demonstrate that MSD0 becomes essential for trafficking of MRP1 when the COOH-terminal region of the protein is mutated. These studies demonstrate that MSD0 and the COOH-terminal region contain redundant trafficking signals, which only become essential when one or the other region is missing or is mutated. These data explain apparent differences in the trafficking requirement for MSD0 and the COOH-terminal region of MRP1 compared with other ABCC proteins.
Mol Biol Cell 2005 May
PMID:Role of the NH2-terminal membrane spanning domain of multidrug resistance protein 1/ABCC1 in protein processing and trafficking. 1577 58

Members of the multidrug resistance-associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter.
Mol Cancer Ther 2005 Apr
PMID:Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. 1582 27

The combination of methylselenocysteine and irinotecan (CPT-11) is synergistic against FaDu and A253 xenografts. Methylselenocysteine/CPT-11 increased tumor cure rate to 100% in FaDu and to 60% in A253. In this study, the effect of methylselenocysteine on pharmacokinetic and pharmacogenetic profiles of genes relevant to CPT-11 metabolic pathway was evaluated to identify possible mechanisms associated with the observed combinational synergy. Nude mice bearing tumors (FaDu and A253) were treated with methylselenocysteine, CPT-11, and a combination of methylselenocysteine/CPT-11. Samples were collected and analyzed for plasma and intratumor concentration of CPT-11 and 7-ethyl-10-hydroxyl-camptothecin (SN-38) by high-performance liquid chromatography. The intratumor relative expression of genes related to the CPT-11 metabolic pathway was measured by real-time PCR. After methylselenocysteine treatment, the intratumor area under the concentration-time curve of SN-38 increased to a significantly higher level in A253 than in FaDu and was associated with increased expression of CES1 in both tumors. Methylselenocysteine/CPT-11 treatment, compared with CPT-11 alone, resulted in a significant decrease in levels of ABCC1 and DRG1 in FaDu tumors and an increase in levels of CYP3A5 and TNFSF6 in A253 tumors. No statistically significant changes induced by methylselenocysteine/CPT-11 were observed in the levels of other investigated variables. In conclusion, the significant increase in the cure rate after methylselenocysteine/CPT-11 could be related to increased drug delivery into both tumors (CES1), reduced resistance to SN-38 (ABCC1 and DRG1) in FaDu, and induced Fas ligand apoptosis (TNFSF6) in A253. No correlation was observed between cure rate and other investigated variables (transporters, degradation enzymes, DNA repair, and cell survival/death genes) in either tumor.
Mol Cancer Ther 2005 May
PMID:Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors. 1589 49

ATP-binding cassette (ABC) membrane proteins comprise a superfamily of transporters with a wide variety of substrates. Humans have 49 members in this superfamily. Several human ABC transporters, such as ABCB1 and ABCC1, have been attributed to cause multidrug resistance (MDR) in cancer treatment when over-expressed. In the past, an MDR cancer cell line MCF7/AdVp3000 has been selected, and overexpression of ABCG2 was thought to cause MDR in this cell line. However, ectopic overexpression of ABCG2 in MCF7 cells could not explain the high drug resistance level observed with the selected cell line. In this study, we designed an AmpArray analysis to profile whether other ABC transporters were also selected to contribute to the increased drug resistance in MCF7/AdVp3000 cells. We found that 16 ABC transporters, including ABCG2, had >/=1.5-fold altered expression in MCF7/AdVp3000 compared with the parental MCF7 cells. In particular, the expression of ABCA4 and ABCC3 was increased by 132- and 459-fold, respectively, whereas ABCG2 was increased by approximately 3000-fold. Furthermore, the elevated expression of these three transporters reversed with the reversed drug resistance phenotype, and silencing ABCC3 expression in MCF7/AdVp3000 cells significantly reduced doxorubicin resistance. Thus, other ABC transporters in addition to ABCG2 are likely to contribute to the MDR selected in MCF7/AdVp3000 cells. This study also shows that AmpArray can be used as a quick and easy tool to profile the expression of ABC transporters in resistant cell lines and tumor samples for potential use in individualized design of therapy.
Mol Pharmacol 2005 Aug
PMID:Expression profiling of ABC transporters in a drug-resistant breast cancer cell line using AmpArray. 1590 50

Multidrug resistance in tumor cells may be caused by reduced drug accumulation resulting from expression of one or more proteins belonging to the ATP-binding cassette (ABC) transporter superfamily. In addition to their drug efflux properties, certain ABC proteins such as multidrug resistance protein 1 (MRP1) (ABCC1) mediate the ATP-dependent transport of a broad array of organic anions. The intrinsically photoreactive glutathione-conjugated cysteinyl leukotriene C4 (LTC4) is a high-affinity physiological substrate of MRP1 and is widely regarded as a model compound for evaluating the substrate binding and transport properties of wild-type and mutant forms of the transporter. In the present study, we have optimized high-level expression of recombinant human MRP1 in Pichia pastoris and developed a two-step purification scheme that results in purification of the transporter to >90% homogeneity. Peptide mapping by matrix-assisted laser desorption ionization/time of flight mass spectrometry of the peptides generated by in-gel protease digestions of purified underglycosylated MRP1 identified 96.7% of the MRP1 sequence with >98% coverage of its 17 transmembrane helices. Subsequent comparisons with mass spectra of MRP1 photolabeled with LTC4 identified six candidate LTC4-modified peptide fragments that are consistent with the conclusion that the intracellular juxtamembrane positions of transmembrane helices 6, 7, 10, 17, and a COOH-proximal portion of the cytoplasmic loop that links the first and second membrane spanning domains are part of the LTC4 binding site of the transporter. Our studies confirm the usefulness of mass spectrometry for analysis of mammalian polytopic membrane proteins and for identification of substrate binding sites of human MRP1.
Mol Pharmacol 2005 Nov
PMID:Analysis of human multidrug resistance protein 1 (ABCC1) by matrix-assisted laser desorption ionization/time of flight mass spectrometry: toward identification of leukotriene C4 binding sites. 1610 87

Formation and transport of glucuronide metabolites were studied in LLC-PK1 cells. Glucuronidation of 17beta-estradiol, 1-naphthol, mycophenolic acid, and 4-methylumbelliferone was examined in microsomes prepared from LLC-PK1 cells, human livers, human kidneys, and human intestines. The rate of glucuronide metabolite formation observed with LLC-PK1 microsomes was comparable to rates observed with various human tissue microsomes. The fate of the glucuronide metabolite formed in the LLC-PK1 cells was studied by examining its extracellular transport using mycophenolic acid as a model substrate. After administration of mycophenolic acid, the amount of the glucuronide metabolite exiting to the extracellular compartments significantly decreased in the presence of MK-571, an inhibitor for the multidrug resistance-associated protein (MRP) transporter. However, the intracellular levels of the glucuronide metabolite did not change, suggesting that MK-571 was probably blocking metabolite efflux. In summary, these results suggest that the glucuronidating enzyme(s) expressed in the LLC-PK1 cells are capable of sufficient glucuronidation activity and that endogenous transporter(s) in LLC-PK1 cells are active and determine the distribution of the formed metabolites. Since these cells have been previously used to study drug transport, they may be a useful tool in future studies to explore the effect of drug transporters on glucuronidation.
Mol Pharm
PMID:Glucuronidation and the transport of the glucuronide metabolites in LLC-PK1 cells. 1619 96

Based upon several previous reports, no consistent relationship between multidrug resistance protein 1 (MRP1, ABCC1) expression and cellular sensitivity to mitoxantrone (MX) toxicity can be ascertained; thus, the role of MRP1 in MX resistance remains controversial. The present study, using paired parental, MRP1-poor, and transduced MRP1-overexpressing MCF7 cells, unequivocally demonstrates that MRP1 confers resistance to MX cytotoxicity and that resistance is associated with reduced cellular accumulation of MX. This MRP1-associated reduced accumulation of MX was partially reversed by treatment of cells with 50 microM MK571 [3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid]-an MRP inhibitor that increased MX accumulation in MRP1-expressing MCF7 cells but had no effect on MRP-poor MCF7 cells. Moreover, in vitro experiments using inside-out membrane vesicles show that MRP1 supports ATP-dependent, osmotically sensitive uptake of MX. Unlike ABCG2 (breast cancer resistance protein, mitoxantrone-resistant protein), MRP1-mediated MX transport is dependent upon the presence of glutathione or its S-methyl analog. In addition, MX stimulates transport of [3H]glutathione. Together, these data are consistent with the interpretation that MX efflux by MRP1 involves cotransport of MX and glutathione. The results suggest that MRP1-like the alternative MX transporters ABCG2 and ABCB1 (MDR1, P-glycoprotein)-can significantly influence tumor cell sensitivity to and pharmacological disposition of MX.
Mol Pharmacol 2006 Apr
PMID:Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. 1643 18

Many studies have been performed with the aim of developing effective resistance modulators to overcome the multidrug resistance (MDR) of human cancers. Potent MDR modulators are being investigated in clinical trials. Many current studies are focused on dietary herbs due to the fact that these have been used for centuries without producing any harmful side effects. In this study, the effect of tetrahydrocurcumin (THC) on three ABC drug transporter proteins, P-glycoprotein (P-gp or ABCB1), mitoxantrone resistance protein (MXR or ABCG2) and multidrug resistance protein 1 (MRP1 or ABCC1) was investigated, to assess whether an ultimate metabolite form of curcuminoids (THC) is able to modulate MDR in cancer cells. Two different types of cell lines were used for P-gp study, human cervical carcinoma KB-3-1 (wild type) and KB-V-1 and human breast cancer MCF-7 (wild type) and MCF-7 MDR, whereas, pcDNA3.1 and pcDNA3.1-MRP1 transfected HEK 293 and MXR overexpressing MCF7AdrVp3000 or MCF7FL1000 and its parental MCF-7 were used for MRP1 and MXR study, respectively. We report here for the first time that THC is able to inhibit the function of P-gp, MXR and MRP1. The results of flow cytometry assay indicated that THC is able to inhibit the function of P-gp and thereby significantly increase the accumulation of rhodamine and calcein AM in KB-V-1 cells. The result was confirmed by the effect of THC on [(3)H]-vinblastine accumulation and efflux in MCF-7 and MCF-7MDR. THC significantly increased the accumulation and inhibited the efflux of [(3)H]-vinblastine in MCF-7 MDR in a concentration-dependent manner. This effect was not found in wild type MCF-7 cell line. The interaction of THC with the P-gp molecule was clearly indicated by ATPase assay and photoaffinity labeling of P-gp with transport substrate. THC stimulated P-gp ATPase activity and inhibited the incorporation of [(125)I]-iodoarylazidoprazosin (IAAP) into P-gp in a concentration-dependent manner. The binding of [(125)I]-IAAP to MXR was also inhibited by THC suggesting that THC interacted with drug binding site of the transporter. THC dose dependently inhibited the efflux of mitoxantrone and pheophorbide A from MXR expressing cells (MCF7AdrVp3000 and MCF7FL1000). Similarly with MRP1, the efflux of a fluorescent substrate calcein AM was inhibited effectively by THC thereby the accumulation of calcein was increased in MRP1-HEK 293 and not its parental pcDNA3.1-HEK 293 cells. The MDR reversing properties of THC on P-gp, MRP1, and MXR were determined by MTT assay. THC significantly increased the sensitivity of vinblastine, mitoxantrone and etoposide in drug resistance KB-V-1, MCF7AdrVp3000 and MRP1-HEK 293 cells, respectively. This effect was not found in respective drug sensitive parental cell lines. Taken together, this study clearly showed that THC inhibits the efflux function of P-gp, MXR and MRP1 and it is able to extend the MDR reversing activity of curcuminoids in vivo.
Mol Cell Biochem 2007 Feb
PMID:Modulation of function of three ABC drug transporters, P-glycoprotein (ABCB1), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCC1) by tetrahydrocurcumin, a major metabolite of curcumin. 1696 Jun 58

Multidrug resistance-associated protein 1 (MRP1) mediates the ATP-dependent efflux of endobiotics and xenobiotics, including estradiol 17-(beta-d-glucuronide), leukotriene C(4), and the reduced glutathione conjugate of 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation. Adriamycin is an effective cancer chemotherapeutic drug whose use is limited by cardiotoxicity. Adriamycin induces oxidative stress and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We investigated the role of Mrp1 in Adriamycin-induced oxidative stress in cardiac tissue. Mice were treated with Adriamycin (20 mg/kg, i.p.), and heart homogenate and sarcolemma membranes were assayed for Mrp1 expression and ATP-dependent transport activity. Expression of Mrp1 was increased at 6 and 24 hours after Adriamycin treatment compared with saline treatment. HNE-adducted proteins were significantly increased (P < 0.001) in the homogenates at 6 hours after Adriamycin treatment and accumulated further with time; HNE adduction of a 190-kDa protein was evident 3 days after Adriamycin treatment. Mrp1 was localized predominately in sarcolemma as shown by confocal and Western blot analysis. Sarcolemma membrane vesicles transported leukotriene C(4) with a K(m) and V(max) of 51.8 nmol/L and 94.1 pmol/min/mg, respectively, and MK571 (10 micromol/L) inhibited the transport activity by 65%. Exposure of HEK(Mrp1) membranes to HNE (10 micromol/L) significantly decreased the V(max) for estradiol 17-(beta-d-glucuronide) transport by 50%. These results show that expression of Mrp1 in the mouse heart is localized predominantly in sarcolemma. Adriamycin treatment increased Mrp1 expression and HNE adduction of Mrp1. Cardiac Mrp1 may play a role in protecting the heart from Adriamycin-induced cardiomyopathy by effluxing HNE conjugates.
Mol Cancer Ther 2006 Nov
PMID:Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice. 1712 32


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