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)

Drug transporters are membrane proteins present in various tissues such as the lymphocytes, intestine, liver, kidney, testis, placenta, and central nervous system. These transporters play a significant role in drug absorption and distribution to organic systems, particularly if the organs are protected by blood-organ barriers, such as the blood-brain barrier or the maternal-fetal barrier. In contrast to neurotransmitters and receptor-coupled transporters or other modes of interneuronal transmission, drug transporters are not directly involved in specific neuronal functions, but provide global protection to the central nervous system. The lack of capillary fenestration, the low pinocytic activity and the tight junctions between brain capillary and choroid plexus endothelial cells represent further gatekeepers limiting the entrance of endogenous and exogenous compounds into the central nervous system. Drug transport is a result of the concerted action of efflux and influx pumps (transporters) located both in the basolateral and apical membranes of brain capillary and choroid plexus endothelial cells. By regulating efflux and influx of endogenous or exogenous substances, the blood-brain barrier and, to a lesser extent the blood-cerebrospinal barrier in the ventricles, represents the main interface between the central nervous system and the blood, i.e., the rest of the body. As drug distribution to organs is dependent on the affinity of a substrate for a specific transport system, membrane transporter proteins are increasingly recognized as a key determinant of drug disposition. Many drug transporters are members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter superfamily or the solute-linked carrier (SLC) class. The multidrug resistance protein MDR1 (ABCB1), also called P-glycoprotein, the multidrug resistance-associated proteins MRP1 (ABCC1) and MRP2 (ABCC2), and the breast cancer-resistance protein BCRP (ABCG2) are ATP-dependent efflux transporters expressed in the blood-brain barrier They belong to the superfamily of ABC transporters, which export drugs from the intracellular to the extracellular milieu. Members of the SLC class of solute carriers include, for example, organic ion transporting peptides, organic cation transporters, and organic ion transporters. They are ATP-independent polypeptides principally expressed at the basolateral membrane of brain capillary and choroid plexus endothelial cells that also mediate drug transport through central nervous system barriers.
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PMID:Membrane transporter proteins: a challenge for CNS drug development. 1711 13

The cytochrome P450 3A4 enzyme and the ABC-transporters may affect the first-pass extraction and bioavailability of drugs and metabolites. Conflicting reports can be found in the literature on the expression levels of efflux transporters in human intestine and how they vary along the intestine. The relative levels of mRNA and protein of CYP3A4 and the ABC tranporters Pgp (ABCB1), MRP1 (ABCC1), and MRP2 (ABCC2) were determined using RT-PCR and Western blot for human intestinal tissues (n = 14) from jejunum, ileum and colon. The expression of mRNA for CYP3A4, Pgp, and MRP2 was highest in jejunum and decreased toward more distal regions, whereas MRP1 was equally distributed in all intestinal regions. For CYP3A4, a more significant correlation could be established between mRNA and protein expression than for the ABC transporters. The samples showed considerable interindividual variability, especially at the protein level. The apically located Pgp and MRP2 showed a similar expression pattern along the human intestine as for CYP3A4. The gene expression of MRP1 exhibited a more uniform distribution.
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PMID:Gene and protein expression of P-glycoprotein, MRP1, MRP2, and CYP3A4 in the small and large human intestine. 1726 54

Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.
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PMID:Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy. 1732 26

Placental ATP-binding cassette (ABC) transporters limit fetal exposure to xenobiotics by regulating transplacental passage into the fetal circulation; their expression and function in fetal membranes, however, has not been studied. In the present study the expression, localisation and function of ABC transporters in human amnion was examined to explore their potential role in modulating amniotic fluid drug disposition in pregnancy. Single-assay oligo-microarrays were used to profile amnion gene expression, and drug transporters expressed at significant levels were identified and selected for further studies. The expression of ABCG2/breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRP) 1 (ABCC1), 2 (ABCC2) and 5 (ABCC5) was detected on the arrays, and verified by RT-PCR and immunoblotting. On confocal microscopy of fetal membrane cryosections, MRP1 and MRP5 were immunolocalised to both apical and basolateral surfaces of the amniotic epithelium, while MRP2 was expressed at low levels only in the apical membrane. BCRP in contrast showed cytoplasmic staining throughout the amniotic epithelium. In addition to the amnion, MRP1 and BCRP immunostaining was observed in the chorion and the decidua. Cell accumulation studies using selective MRP and BCRP inhibitors showed the transporters to be functionally active in amnion epithelial monolayer cultures. In contrast, transwell transport studies using intact amnion membranes did not show significant vectorial transport. These findings identify the amnion as a novel site of ABC drug transporter expression. Functional studies indicate that they may act primarily to prevent cellular xenobiotic accumulation, rather than to confer fetal protection through reduced accumulation in amniotic fluid.
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PMID:Expression, localisation and activity of ATP binding cassette (ABC) family of drug transporters in human amnion membranes. 1748 62

Simultaneous use of nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and other drugs has been reported to delay the plasma elimination of methotrexate in patients. Previously, we have reported that inhibition of the uptake process cannot explain such drug-drug interactions using rats. The present study quantitatively evaluated the possible role of the transporters in such drug-drug interactions using human kidney slices and membrane vesicles expressing human ATP-binding cassette (ABC) transporters. The uptake of methotrexate by human kidney slices was saturable with a K(m) of 45 to 49 microM. Saturable uptake of methotrexate by human kidney slices was markedly inhibited by p-aminohippurate and benzylpenicillin, but only weakly by 5-methyltetrahydrofolate. These transport characteristics are similar to those of a basolateral organic anion transporter (OAT) 3/SLC22A8. NSAIDs and probenecid inhibited the uptake of methotrexate by human kidney slices, and, in particular, salicylate, indomethacin, phenylbutazone, and probenecid were predicted to exhibit significant inhibition at clinically observed plasma concentrations. Among ABC transporters, such as BCRP/ABCG2, multidrug resistance-associated protein (MRP) 2/ABCC2, and MRP4/ABCC4, which are candidates for the luminal efflux of methotrexate, ATP-dependent uptake of methotrexate by MRP4-expressing membrane vesicles was most potently inhibited by NSAIDs. Salicylate and indomethacin were predicted to inhibit MRP4 at clinical plasma concentrations. Diclofenac-glucuronide significantly inhibited MRP2-mediated transport of methotrexate in a concentration-dependent manner, whereas naproxen-glucuronide had no effect. Inhibition of renal uptake (via OAT3) and efflux processes (via MRP2 and MRP4) explains the possible sites of drug-drug interaction for methotrexate with probenecid and some NSAIDs, including their glucuronides.
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PMID:Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices. 1757 1

The role of uptake and efflux transport proteins in the tissue distribution of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its metabolites is largely unknown. Carbonyl reduction of NNK results in formation of the carcinogenic 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which in rats is glucuronidated to the non-toxic NNAL-O-glucuronide. Previous in vitro studies showed that NNAL-O-glucuronide is a substrate for the human ATP-binding cassette transport proteins multidrug resistance protein (MRP)1 (ABCC1) and MRP2 (ABCC2). To investigate the influence of Mrp2 deficiency on NNK biotransformation and biliary excretion, [(3)H]NNK was administered intravenously to bile duct-cannulated wild-type (WT) and Mrp2-deficient (TR(-)) Wistar rats; plasma, bile and urine samples were collected for 5 h and analyzed by high-pressure liquid chromatography with radiochemical detection. The total radioactivity recovered in WT and TR(-) bile was 12 and 7% of the dose, respectively. NNAL-O-glucuronide accounted for 87% of the radioactivity in WT bile but was not detected in TR(-) bile. Urinary recovery of 1-(3-pyridyl)-1-butanol-4-carboxylic acid (hydroxy acid), NNAL-O-glucuronide and NNAL-N-oxide from 2-5 h was greater in TR(-) compared with WT rats. NNK plasma clearance was significantly higher in TR(-) (115 +/- 23 ml/min/kg) compared with WT (48 +/- 13 ml/min/kg) rats. A higher concentration and/or earlier appearance of hydroxy and 1-(3-pyridyl)-1-butanone-4-carboxylic acids, NNAL-N-oxide and NNK-N-oxide, and decreased NNK and NNAL concentrations in TR(-) plasma suggested increased cytochrome P450 biotransformation in TR(-) rats. The total recovery of hydroxy acid in bile and urine was significantly higher in TR(-) compared with WT rats. Thus, Mrp2 is responsible for the biliary excretion of NNAL-O-glucuronide and Mrp2 deficiency results in increased formation of carcinogenic NNK metabolites.
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PMID:Biotransformation and transport of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in bile duct-cannulated wild-type and Mrp2/Abcc2-deficient (TR ) Wistar rats. 1772 74

Olmesartan, a novel angiotensin II AT1-receptor antagonist, is excreted into both bile and urine, with minimal metabolism. Because olmesartan is a hydrophilic anionic compound, some transporters could be involved in its hepatic and renal clearance. In this study, we characterized the role of human drug transporters in the pharmacokinetics of olmesartan and determined the contribution of each transporter to the overall clearance of olmesartan. Olmesartan was significantly taken up into human embryonic kidney 293 cells expressing organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, and OAT3. We also observed its saturable uptake into human hepatocytes and kidney slices. Estimated from the relative activity factor method and application of specific inhibitors, the relative contributions of OATP1B1 and OATP1B3 to the uptake of olmesartan in human hepatocytes were almost the same, whereas OAT3 was predominantly involved in its uptake in kidney slices. The vectorial transport of olmesartan was observed in OATP1B1/multidrug resistance-associated protein (MRP) 2 double transfectants, but not in OATP1B1/multidrug resistance (MDR) 1 and OATP1B1/breast cancer resistance protein (BCRP) transfectants. ATP-dependent transport into membrane vesicles expressing human MRP2 and MRP4 was clearly observed, with K(m) values of 14.9 and 26.2 microM, respectively, whereas the urinary excretion of olmesartan in Mrp4-knockout mice was not different from that of control mice. We also investigated the transcellular transport of olmesartan medoxomil, a prodrug of olmesartan. Vectorial basal-to-apical transport was observed in OATP1B1/MRP2, OATP1B1/MDR1 double, and OATP1B1/BCRP double transfectants, suggesting the possible involvement of MRP2, MDR1, and BCRP in the limit of intestinal absorption of olmesartan medoxomil. From these results, we suggest that multiple transporters make a significant contribution to the pharmacokinetics of olmesartan and its prodrug.
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PMID:Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. 1782 33

Bioluminescence imaging (BLI) is becoming indispensable to the study of transgene expression during development and, in many in vivo models of disease such as cancer, for high throughput drug screening in vitro. Because reaction of d-luciferin with firefly luciferase (fLuc) produces photons of sufficiently long wavelength to permit imaging in intact animals, use of this substrate and enzyme pair has become the method of choice for performing BLI in vivo. We now show that expression of the ATP-binding cassette (ABC) family transporter ABCG2/BCRP affects BLI signal output from the substrate d-luciferin. In vitro studies show that d-luciferin is a substrate for ABCG2/BCRP but not for the MDR1 P-glycoprotein (ABCB1/Pgp), multidrug resistance protein 1 (MRP1/ABCC1), or multidrug resistance protein 2 (MRP2/ABCC2). d-Luciferin uptake within cells is shown to be modulated by ABC transporter inhibitors, including the potent and selective ABCG2/BCRP inhibitor fumitremorgin C. Images of xenografts engineered to express transgenic ABCG2/BCRP, as well as xenografts derived from the human prostate cancer cell line 22Rv1 that naturally express ABCG2/BCRP, show that ABCG2/BCRP expression and function within regions of interest substantially influence d-luciferin-dependent bioluminescent output in vivo. These findings highlight the need to consider ABCG2/BCRP effects during d-luciferin-based BLI and suggest novel high throughput methods for identifying new ABCG2/BCRP inhibitors.
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PMID:ABCG2/BCRP expression modulates D-Luciferin based bioluminescence imaging. 1790 48

Clinically relevant resistance to the currently approved camptothecins, irinotecan and topotecan, is poorly understood but may involve increased expression of ATP-dependent drug transporters such as ABCG2 (breast cancer resistant protein, BCRP). Gimatecan (ST1481) is a lipophilic 7-substituted camptothecin derivative that exhibits potent anti-tumor activity in a variety of preclinical cancer models and is under investigation in the clinic. Previous studies reported that gimatecan cytotoxicity was not affected by expression of ABCG2. To confirm and extend this finding, we assessed the cytotoxicity of gimatecan in pairs of isogenic cell lines consisting of transfectants expressing either ABCG2 (including wild-type, R482T, or R482G mutants), ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2), or ABCC4 (MRP4). Expression of wild-type or mutant ABCG2 in human cell lines conferred resistance to topotecan but not to gimatecan. Similarly, intracellular accumulation of gimatecan was unaffected by expression of wild-type ABCG2. Furthermore, expression of P-glycoprotein or MRP2 did not alter gimatecan cytotoxicity. Whereas expression of MRP1 had a minor effect on gimatecan cytotoxicity, expression of ABCC4 was found to significantly reduce the anti-proliferative effects of this drug. Cells containing resistance-conferring mutations in topoisomerase I were also resistant to gimatecan. These results suggest that gimatecan may be more effective than irinotecan or topotecan in cancers that express ABCG2, but not in cancers that express high levels of ABCC4 or contain certain topoisomerase I (TOP1) mutations.
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PMID:Effects of drug efflux proteins and topoisomerase I mutations on the camptothecin analogue gimatecan. 1794 30

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


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