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)

We investigated the expression of multidrug resistance-associated protein (MRP) in 115 cases of head and neck squamous cell carcinoma (H&NSCC) by immunohistochemistry and examined the relationship between MRP expression and clinical factors. Thirty-four (30%) of 115 cases of H&NSCC had expression of MRP. The clinical stage was inversely associated with the expression of MRP (P = 0.0090), but not with age, sex, tumor size, metastasis, recurrence, death from disease or overall survival rate for 5 years. In vitro chemosensitivity to five chemotherapeutic agents (cis-diamminedichloroplatinum, 5-fluorouracil, peplomycin, mitomycin C and Adriamycin) was tested by ATP assay and no correlation between the sensitivity of tumor cells to the cytotoxicity of any drug and MRP expression was found. These results suggest that the resistance to anticancer drugs is not dependent only on the expression of MRP in H&NSCC.
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PMID:Expression of multidrug resistance-associated protein (MRP) in head and neck squamous cell carcinoma. 956 53

Eisai hyperbilirubinemic (EHB) rats, a new mutant strain inbred from Sprague-Dawley (SD) rats, show no inherent expression of the canalicular multidrug resistance protein (cMrp) and lack canalicular multispecific organic anion transporter (cMOAT) activity. A sample of 203Hg (40 microCi with 40 microg Hg/kg) was injected intravenously (i.v.) into four male SD and EHB rats. Biliary excretion of reduced-glutathione (GSH) was 426 and 2 microg/bile for 15 min in the SD and EHB rats, respectively. Biliary excretion of 203Hg for 45 min in EHB rats significantly decreased to 1/4 of that of the SD rats. However, there was no difference in the hepatic uptake of 203Hg between the two strains. Other rats were injected subcutaneously (s.c.) with HgCl2 solution (at 0.2 and 1.6 mg/kg) containing 203Hg. Some 4 days after the injection of 0.2 mg/kg, about 3 and 13% of the total dose was found in the liver in SD and EHB rats, respectively. The hepatic supernatant Hg was recovered mainly in the void volume of a Sephadex column. Some 2 days after the injection of 1.6 mg/kg, these values were 3 and 23% in SD and EHB rats, respectively. The increased retention stimulated hepatic metallothionein (MT) induction and increased the proportion of Hg in the MT region on the Sephadex column. On the other hand, biliary excretion of 203Hg for 15 min in EHB rats was about 1/6-1/4 of that in SD rats. With the injection of 1.6 mg/kg, hepatic and renal functions worsened in EHB rats. In particular, severe necrosis was found in the renal tubules. Our results suggest that biliary secretion of inorganic Hg may be partly regulated by the ATP-dependent transport system, the glutathione S-conjugate export pump (GS-X pump) composed of Mrp and MOAT. Significantly decreased excretion stimulates hepatic retention of inorganic Hg. However, the hepatic lesions are less predictive. The MT induction may reduce the toxicity of metal to the liver cells.
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PMID:Decreased hepatobiliary secretion of inorganic mercury, its deposition and toxicity in the Eisai hyperbilirubinemic rat with no hepatic canalicular organic anion transporter. 958 89

The mechanism for cisplatin resistance in cisplatin-resistant KCP-4 cells was studied. Although multidrug resistance-associated protein (MRP) was not detected in KCP-4 cells, the cells were more resistant to heavy metals than multidrug-resistant C-A120 cells that overexpressed MRP. KCP-4 cells expressed metallothionein, but it was scarcely involved in cisplatin resistance in these cells. KCP-4 cells did not express canalicular multispecific organic anion transporter (cMOAT). The glutathione (GSH) level was 4.7-fold higher in KCP-4 cells than in KB-3-1 cells. When the GSH level in KCP-4 cells was decreased by treating the cells with buthionine sulfoximine and nitrofurantoin, the accumulation of and sensitivity to cisplatin in the cells were increased. C-A120 cells were only 3.0-fold more resistant to cisplatin than KB-3-1 cells and this resistance was not affected by the increased glutathione level. The accumulation of platinum in C-A120 and KCP-4 cells was 68.5 and 20.4% of that in KB-3-1 cells, respectively, while the intracellular levels of antimony potassium tartrate in C-A120 and KCP-4 cells were 13.2 and 9.9% of that in KB-3-1 cells, respectively. The ATP-dependent efflux of antimony was enhanced in both C-A120 and KCP-4 cells. These results, taken together, suggest an efflux pump for heavy metals different from MRP and cMOAT is involved in cisplatin resistance in KCP-4 cells.
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PMID:An active efflux system for heavy metals in cisplatin-resistant human KB carcinoma cells. 959 4

Membrane vesicles prepared from cells expressing the multidrug resistance-associated protein (MRP) transport glutathione S-conjugates of hydrophobic substrates in an ATP dependent manner. Purified MRP possesses ATPase activity which can be further stimulated by anticancer drugs or leukotriene C4. However, the detailed relationship between ATP hydrolysis and drug transport has not been established. How the ATPase activity of MRP is regulated in the cell is also not known. In this report, we have examined the effects of different nucleotides on the ATPase activity of purified MRP. We have found that pyrimidine nucleoside triphosphates have little effect on enzymatic activity. In contrast, purine nucleotides dATP, dGTP, and adenosine 5'-(beta,gamma-imido)triphosphate function as competitive inhibitors. Somewhat unexpectedly, low concentrations of all the nucleoside diphosphates (NDPs) tested, except UDP, stimulate the ATPase activity severalfold. ADP or GDP at higher concentrations was inhibitory, reflecting NDP binding to the substrate site. On the other hand, the enhancement of hydrolysis at low NDP concentrations must reflect interactions with a separate site. Therefore, we postulate the presence of at least two types of nucleotide binding sites on the MRP, a catalytic site(s) to which ATP preferentially binds and is hydrolyzed and a regulatory site to which NDPs preferentially bind and stimulate hydrolysis. Interestingly, the stimulatory effects of drugs transported by MRP and NDPs are not additive, i.e. drugs are not able to further stimulate the NDP-activated enzyme. Hence, the two activation pathways intersect at some point. Since both nucleotide binding domains of MRP are likely to be required for drug stimulation of ATPase activity, the two sites that we postulate may also involve both domains.
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PMID:Stimulation of ATPase activity of purified multidrug resistance-associated protein by nucleoside diphosphates. 972 96

To investigate the possible involvement of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and/or other glutathione S-conjugate export pump (GS-X pump) family members on the active efflux of irinotecan [(7-ethyl-10-[4-(1-piperidino)-1-pipertidino)-1-piperidino]carb onylox y camptothecin (CPT-11)] and its metabolites, as well as their contribution to the acquisition of resistance, we studied the uptake of CPT-11, its active metabolite SN-38, and glucuronide conjugate (SN38-Glu) using membrane vesicles from human epidermoid KB-3-1-derived cell lines. These lines included KB-C2, C-A500, and KCP-4, which overexpress P-gp, MRP, and the unidentified GS-X pump, respectively. The carboxylate form of SN-38 exhibited significant ATP-dependent transport, with a Michaelis constant of 17 microM, into membrane vesicles from C-A500 but not from other cell lines. Among these KB-derived cells, significant ATP-dependent uptake of the carboxylate form of CPT-11 was only observed in KB-C2 vesicles. In addition, the uptake of the lactone and carboxylate forms of SN38-Glu into membrane vesicles from C-A500 and KB-C2, but not KCP-4, was ATP dependent, although the transport activity in C-A500 was much higher than that in KB-C2. The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay revealed that the resistance of KB-C2 to CPT-11 and SN-38, compared with that of KB-3-1, was 6.3- and 6.8-fold, respectively; the corresponding figures for C-A500 were 12- and 27-fold, respectively, whereas those for KCP-4 were 2.3- and 20-fold, respectively. These results suggest that MRP and P-gp are involved in the active efflux of SN-38 and CPT-11, respectively, from human KB-derived cells. In addition, a difference in substrate specificity among GS-X pump members was demonstrated.
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PMID:Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. 991 83

Acute myelogenous leukemia (AML) represents 80% of adult acute leukemias. A standard-dose chemotherapy allows to obtain 52% to 72% of complete remission (CR). A major limitation for success in chemotherapy of AML is dominance of drug-resistant subpopulations of cells. Cytosine-arabinoside (Ara-C) is a basic drug in AML treatment. Myeloblasts resistance to Ara-C could be kinetic or pharmacological. The classical multidrug resistance (MDR) depends on presence in resistant myeloblasts ATP-dependent drug-efflux pump with ability to remove cytotoxic drugs from the cells. It is a product of MDR1 gene called P-glycoprotein (Pgp). Pgp is responsible for cell resistance to cytotoxic compounds of natural origin, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, colchicine and amsacrine. There were also identified not Pgp-dependent multidrug resistance mechanisms (non-Pgp MDR) in AML. All mentioned above drugs are involved but not taxol. Non-Pgp MDR depends on topoisomerase II alfa activity alterations, multidrug resistance-associated protein (MRP) expression and lung resistance-related protein (LRP) expression. Pgp positive AML patients have poorer complete remission (CR) rate, decreased remission duration and overall survival. Pgp expression is detected among 70% AML patients older than 55. The most promising drugs in circumventing classical MDR seems cyclosporin A (CsA) and cyclosporin D (SDZ PCS 833). They are successfully used in refractory and relapsed AML.
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PMID:[The causes of treatment ineffectiveness in acute myelogenous leukemia--the role of blast resistance to cytotoxic drugs]. 1002 86

This review considers the mechanisms associated with the pleiotropic resistance of cancer cells to chemotherapeutic drugs, and more particularly those related to intracellular pH (pHi). The multidrug resistance (MDR) phenomenon responsible for the decreased accumulation and increased efflux of cytotoxic drugs is generally associated with excess levels of P-glycoproteins (Pgps) encoded by MDR genes and/or the multidrug resistance-associated protein (MRP). MDR cell lines, derived from normal or tumor cells, frequently exhibit abnormally elevated pHi and changes in the production of various proteins. Recent studies have suggested that, in addition to the impact of the ATP-dependent membrane transporters Pgp and MRP on drug transport, other mechanisms linked to pHi changes in MDR cells may play an important role in drug resistance. We have shown that alkalinization of the acidic compartments (endosomes and lysosomes) by lysosomotropic agents could stimulate the efflux of vinblastine from drug-resistant mouse renal proximal tubule cells. The fact that weak base chemotherapeutic drugs can be sequestered within the acidic organelles of MDR cells sheds new light on the cellular mechanisms of drug resistance.
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PMID:Mechanisms of altered sequestration and efflux of chemotherapeutic drugs by multidrug-resistant cells. 1040 56

Overexpression of ATP-dependent drug efflux pumps, P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP), confers multidrug resistance to tumor cells. Modulators of multidrug resistance block the action of these pumps, thereby sensitizing cells to oncolytics. A potent Pgp modulator is LY335979, which fully sensitizes Pgp-expressing cells at 0.1 microM in cytotoxicity assays and for which Pgp has an affinity of 59 nM. The present study examines its effect on MRP1-mediated drug resistance and cytochrome P-450 (CYP) activity and its ability to serve as a Pgp substrate. Drug resistance was examined with HL60/ADR and MRP1-transfected HeLa-T5 cells. Drug cytotoxicity was unaffected by 1 microM LY335979; leukotriene C4 uptake into HeLa-T5 membrane vesicles was unaffected. Because the substrate specificity of Pgp and CYP3A overlap, the effect of LY335979 on the 1'-hydroxylation of midazolam by CYP3A in human liver microsomes was examined. The apparent K(i) was 3.8 microM, approximately 60-fold higher than the affinity of Pgp for LY335979. The modulator's effect on Pgp was evaluated with Pgp-overexpressing CEM/vinblastine (VLB)(100) and parental CCRF-CEM cells. Both cell lines accumulated [(3)H]LY335979 equally well and did not efflux [(3)H]LY335979 during a 3-h incubation, indicating that it is not a substrate of Pgp. Equilibrium-binding studies with CEM/VLB(100) plasma membranes and [(3)H]LY335979 showed that Pgp had a K(d) of 73 nM, which is in good agreement with the previously determined K(i) value. Thus, LY335979 is an extremely potent Pgp, and not MRP1 or MRP2, modulator and has a significantly lower affinity for CYP3A than for Pgp.
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PMID:Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. 1041 2

Several organic anions are actively extruded from intestinal epithelial cells into the lumen and vascular sides. To examine the role of the multidrug resistance-associated protein (MRP) family in the intestinal efflux of organic anions, the function and expression of these proteins were investigated with Caco-2, a human adenocarcinoma cell line that retains many of the characteristics of normal enterocytes. [(3)H]2,4-Dinitrophenyl-S-glutathione (DNP-SG) and [(3)H]17beta-estradiol 17-beta-D-glucuronide (E(2)17betaG), typical substrates for MRP1 and cMOAT (canalicular multispecific organic anion transporter)/MRP2, were taken up into brush-border membrane vesicles (BBMVs) from Caco-2 in an ATP-dependent manner, with K(m) values of 16.9 +/- 7.2 and 9.4 +/- 1.2 microM, respectively. The uptake of [(3)H]DNP-SG into BBMVs was osmotically sensitive and stimulated to some extent by other nucleotide triphosphates (GTP, CTP, and UTP) but not by ADP or AMP. An ATPase inhibitor, vanadate, inhibited the ATP-dependent uptake of [(3)H]DNP-SG to some extent. Reverse-transcriptase polymerase chain reaction resulted in the amplification of MRP1, MRP3, and MRP5. Northern blot analysis indicated extensive expression of cMOAT/MRP2 and MRP3 and only minimal expression of MRP1 and MRP5. Although cMOAT/MRP2 was continuously expressed throughout the culture period, MRP3 was not expressed immediately after the confluent state was reached. Collectively, the presence of ATP-dependent transport systems for DNP-SG and E(2)17betaG was demonstrated in Caco-2 cells. Because cMOAT/MRP2 and MRP3 may be expressed on brush-border and basolateral membranes in epithelial cells, respectively, the transport activity associated with BBMVs may result from the function of cMOAT/MRP2.
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PMID:Function and expression of multidrug resistance-associated protein family in human colon adenocarcinoma cells (Caco-2). 1060 57

Among tumoral resistances, multidrug resistance (MDR) is characterized as cross-resistance to a variety of structurally and functionally unrelated drugs such as vinca alkaloids, colchicine, and anthracyclines. Decreased drug cellular influx and increased cellular ability for drug extrusion are the main mechanisms involved in MDR. Two plasma membrane proteins, p-glycoprotein (p-gp) and the multidrug resistance-associated protein (MRP), act as ATP-dependent cellular efflux. Furthermore, protein kinase C (PKC) is also central to MDR. The present study reviews the role of cholesterol and other lipids in the reduction of drug influx and drug binding to cellular membranes. The study also examines the effect of lipid composition on p-gp activity. Concerning the role of PKC in MDR, two phospholipases involved in diacylglycerol (DG) production increase in MDR cells. These are phosphatidylinositol-4, 5-bisphosphate-specific phospholipase C and phosphatidylethanolamine-specific phospholipase D. A positive feedback mechanism for DG production which includes these phospholipases, a phosphatidylcholine-specific phospholipase C and a phosphatidylcholine-specific phospholipase A2 has also been suggested. The hypothesis of exocytic involvement in MDR is reviewed, and some lipid changes found in MDR cells are interpreted according to those fusogenic properties normally involved in exocytic transport. Also, the possible role of lipid mediators, such as phosphatidic acid and platelet-activating factor, is examined.
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PMID:Lipids: A key role in multidrug resistance? (Review). 1071 49


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