Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of the nonlinear concentration dependence of intestinal absorption of the 5-hydroxytryptamine receptor antagonist azasetron was studied by use of rat in situ intestinal perfusion, as well as an in vitro Ussing-type chamber method mounted with rat intestinal tissue and cultured monolayers of human adenocarcinoma Caco-2 cells. The intestinal absorption rate constant of azasetron evaluated by the Doluisio method increased significantly with increasing concentration of azasetron up to 10 mM in a nonlinear fashion and tended to decrease at higher concentrations. Mucosal-to-serosal directed permeation of [14C]azasetron across rat ileal sheets evaluated by the in vitro Ussing-type chamber method also increased in a nonlinear fashion in a low concentration range, followed by a decrease as the concentration was further increased, whereas serosal-to-mucosal directed permeation decreased in a concentration-dependent manner. Vectorial transport of [14C]azasetron across a Caco-2 cell monolayer was observed, with higher transport in the basolateral-to-apical direction at a trace concentration of azasetron. When the initial uptake rate of azasetron by Caco-2 cells was measured, it was saturable with an apparent half-saturation concentration of 15 mM and was reduced in the presence of several cationic compounds. These observations suggest that azasetron is taken up by a carrier-mediated transport mechanism across the intestinal epithelial cells. When the steady-state uptake of [14C]azasetron was measured, it was increased in the presence of unlabeled azasetron and ondansetron. In addition, the steady-state uptake was enhanced in the presence of a P-glycoprotein inhibitor, cyclosporin A, and by ATP-depletion of the cells, although these treatments had no effect on the initial uptake of [14C]azasetron. Furthermore, the multidrug-resistant cancer cell line K562/ADM that overexpresses P-glycoprotein accumulated azasetron less extensively than did the parental drug-sensitive K562 cells. These results strongly suggest that azasetron is secreted into the intestinal lumen predominantly by P-glycoprotein. We conclude that intestinal transport of azasetron involves specialized transporters in both the absorptive and secretory directions, and the complex nonlinear intestinal absorption characteristics can be ascribed to the participation of multiple transport mechanisms.
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PMID:Nonlinear intestinal absorption of 5-hydroxytryptamine receptor antagonist caused by absorptive and secretory transporters. 933 14

We have demonstrated that low-level expression of P-glycoprotein (PGP), detectable by reverse transcriptase polymerase chain reaction (RT-PCR) assay and flow cytometric assay, is an important factor in multidrug resistance (MDR) in ACHN cancer cells. In this study, we established a subline highly resistant to adriamycin (ACHN/ADM) from ACHN cells, and determined the correlation between PGP levels and MDR levels using ACHN/ADM cells and their parent ACHN cells. The ACHN/ADM cells showed overexpression of PGP, and sensitivity to antitumor agents was lower than that found in ACHN cells. Intracellular accumulation of ADM in ACHN/ADM cells was approximately half the amount of its accumulation in ACHN cells. Sensitivity to ADM in ACHN/ADM cells was enhanced by chemosensitizers with an increase in intracellular ADM accumulation. These results indicate that PGP levels correlate with MDR levels and suggest that chemotherapy using chemosensitizers might be effective in the treatment of renal cancers with overexpression of PGP.
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PMID:Correlation of expression levels of P-glycoprotein with resistance to adriamycin in a renal adenocarcinoma cell line. 944 50

To overcome the problem of multidrug resistance, we investigated the effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells. Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS-treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed with sense or random control oligonucleotides. The expression of mdr1 mRNA in K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the random control. Intracellular rhodamine retention and [3H]daunorubicin also increased after antisense treatment. Chemosensitivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucleotides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia.
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PMID:Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene (mdr1) antisense oligonucleotides. 955 71

To clarify the mechanistic role of PGP (P-glycoprotein) in multidrug transport, we constructed a kinetic model composed of four compartments: (1) the extracellular space; (2) the space in the membrane; (3) the intracellular space; and (4) the pore-like space in the PGP molecule. The kinetics of the concentration of ADM (adriamycin) in each compartment were formulated based on the assumptions that (a) the movement of ADM between two compartments by diffusion is dependent on a dynamic distribution coefficient introduced here, (b) the uptake of ADM into the pore-like structure by the pump mechanism activated by ATP is described by enzyme kinetics, (c) the movement of ADM out of the pore-like structure to the extracellular medium through a valve-like mechanism is also expressed by enzyme kinetics. The mathematical analysis of the exact solution can explain the distinct effects of verapamil and vanadate on the accumulation and release of ADM, where verapamil inhibits the efflux by the valve-like mechanism and vanadate blocks the influx by the pump mechanism. We also performed a numerical calculation with this model for a quantitative explanation and found the valid parameter values to fit the experimental data. These results support the modified hydrophobic vacuum cleaner model.
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PMID:Kinetic analysis of the mechanism of action of the multidrug transporter. 982 64

The distribution of HSR-903, a new quinolone antibacterial agent, to the brain after i.v. administration to rats was low compared with that to other tissues. The blood-brain barrier permeability to HSR-903 determined by the brain perfusion method was low, and increased nonlinearly with increasing concentration of HSR-903 in the perfusate. When the brain-to-plasma concentration ratio (Kp, brain) was measured in mdr1a gene-knockout mice, the value was 8 times higher than that in normal mice. The uptake of [14C]HSR-903 by multidrug-resistant K562/ADM cells, which express P-glycoprotein (P-gp), was significantly lower than that by the drug-sensitive parent K562 cells. In addition, the uptake of [14C]HSR-903 by K562/ADM cells was significantly increased in the presence of cyclosporin A and ATP-depleting agents. These observations support the idea that P-gp participates in HSR-903 efflux from the brain. The steady-state uptake of HSR-903 by a monolayer of primary cultured bovine brain capillary endothelial cells was increased in the presence of several quinolone antibacterial agents or anionic compounds, such as 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, and in bicarbonate ion-free medium, as well as by P-gp inhibitors (cyclosporin A and quinidine). These results suggested that the efflux of HSR-903 proceeds at least partly via an anion-sensitive efflux transport mechanism as well as via P-gp. In conclusion, the low brain distribution of the new quinolone antibacterial agent HSR-903 can be ascribed to multiple efflux mechanisms including P-gp and an unidentified anion-sensitive transporter operating in the brain capillary endothelial cells that constitute the blood-brain barrier.
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PMID:Efflux transport of a new quinolone antibacterial agent, HSR-903, across the blood-brain barrier. 1038 59

A 43-year-old female underwent muscle preserving mastectomy with 6 cycles of adjuvant CMF chemotherapy for breast cancer. She developed multiple lung metastases 16 months later. The metastases were refractory to 3 cycles of CAF administration, and worsened (PD). We therefore added high-dose toremifene to her treatment. This combination therapy brought a marked decrease in the lung metastases. After 9 cycles of CAF with high-dose toremifene therapy, lung metastatic findings had almost disappeared from her chest X-ray. Following this treatment, UFT and toremifene were orally administered for maintenance therapy. Thirty-two months later at present, no increase in these lesions has been observed. High-dose antiestrogen drugs have the potential to inhibit P-glycoprotein. The combination of high-dose toremifene with CAF is potentially effective against ADM-resistant breast cancer.
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PMID:[A case of breast cancer patient of CAF (cyclophosphamide, adriamycin, 5-fluorouracil) resistant lung metastasis with remarkable response to reverse drug-resistance by toremifene]. 1043 84

P-glycoprotein (p-gp), a drug transporter in multidrug-resistant cancer cells, is a transmembrane protein encoded by mdr1a, mdr1b and mdr2 genes in mice. In our previous report, high level p-gp was immunohistochemically detected in capillary endothelial cells of the guinea pig inner ear, supporting a possible role as an extrusion pump in the blood-inner ear barrier (BIB). We investigated the functional involvement of p-gp in the inner ear using mdr1a gene knock-out mice [mdr1a(-/-) mice]. Pharmacokinetic analyses showed that mdr1a(-/-) mice displayed obviously increased accumulations of the p-gp-transported drugs doxorubicin (adriamycin, ADM) and vinblastine in the inner ear tissues compared with those in mdr1a(+/+) mice. Subsequent functional studies using auditory-evoked brainstem responses showed hearing impairment only in mdr1a(-/-) mice after administering these drugs. Furthermore, inhibition of p-gp function by co-administration of cyclosporin A (CsA) with doxorubicin (ADM) in mdr1a(+/+) mice resulted in increased accumulation of ADM in inner ear tissues and hearing impairment similar to that noted in mdr1a(-/-) mice. We conclude that mdr1a p-gp, which acts as an efflux pump in the inner ear, prevents ototoxicity induced by p-gp substrate drugs and contributes to a new functional mechanism in the BIB.
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PMID:Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear barrier in mice. 1066 3

MDR results from overexpression of P-glycoprotein (Pgp) and multidrug resistance protein (MRP or MRP1) that function as ATP-dependent efflux pumps. Lung resistance related protein (LRP) is also supposed to be involved in MDR. The human canalicular multispecific organic anion transporter (cMOAT) gene that is responsible for the defects in Dubin-Johnson syndrome was isolated. cMOAT is homologous to MRP1 and supposed to be involved in drug resistance. Human cMOAT cDNA transfected LLC-PK1 cells, LLC/cMOAT-1, have increased resistance to vincristine (VCR), 7-ethyl-10-hydroxycamptothecin (SN-38), and cisplatin. The multidrug resistance (MDR)-reversing agents, cyclosporin A (CsA) and PAK-104P, almost completely reversed the resistance to VCR, SN-38 and cisplatin of LLC/cMOAT-1 cells by interacting with the substrate binding site of cMOAT. Treatment of human colorectal carcinoma SW-620 cells with sodium butyrate(NaB) induced LRP in the cells and conferred resistance to Adrianycin(ADM), VCR, VP-16, gramicidin D and taxol. Two LRP-specific ribozymes inhibited the NaB-induced expression of LRP in SW-620 cells and almost completely abolished their acquisition of the MDR phenotype. The accumulation of ADM, VCR and taxol was not decreased in NaB-treated cells, suggesting that ATP-binding cassette transporters are not involved in the MDR of NaB-treated cells. ADM was mainly located in the nuclei of untreated and the cytoplasm of NaB-treated cells. The accumulation level of ADM in the nuclei isolated from untreated cells or those from treated cells in the presence of anti-LRP polyclonal antibody was higher than that from treated cells in the absence of the antibody. Efflux of ADM from nuclei isolated from NaB-treated cells was enhanced compared with those from untreated cells and NaB-treated cells transfected with a LRP-specific ribozyme. The polyclonal antibody against LRP inhibited the enhanced efflux of ADM from nuclei isolated from NaB-treated cells. These findings indicate that LRP is involved in resistance to ADM, VCR, VP-16, taxol and gramicidin D, and has an important role in the transport of ADM from the nucleus to the cytoplasm.
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PMID:[Mechanisms for resistance to anticancer agents and the reversal of the resistance]. 1069 15

The non-ionic detergent Tween 80, which is used as a solvent for lipophilic drugs such as VP-16 and Taxotere, was found to reverse VP-16 resistance of the P-glycoprotein-associated multidrug resistance phenotype via increasing VP-16 influx. In adriamycin-resistant human chronic myelogenous leukemia K562 cells (K562/ADM), which overexpress mdr1 mRNA, the accumulation of VP-16 was only about 10% that in wild-type K562 cells. Tween 80 enhanced VP-16 accumulation in K562/ADM cells but did not influence VP-16 accumulation in parental K562 cells. VP-16 efflux was rapid and similar in both sensitive and resistant cell lines and was not blocked by Tween 80 or verapamil. Under glucose-free conditions, VP-16 accumulation in K562/ADM cells was only half of that in K562 cells. Tween 80 increased VP-16 accumulation in K562/ADM cells in glucose-free medium. In growth inhibition assay, Tween 80 reversed K562/ADM sensitivity to VP-16 without cell damage. Taken together, Tween 80 reverses VP-16 sensitivity in multidrug-resistant K562 cells by increasing influx, which is considered to be the primary mechanism of VP-16 resistance in K562/ADM cells.
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PMID:Non-ionic detergent Tween 80 modulates VP-16 resistance in classical multidrug resistant K562 cells via enhancement of VP-16 influx. 1073 19

The effect of an aureolic acid, mithramycin (MTM) on multidrug resistance (MDR) was investigated. At a concentration of 0.02--0.1 mg/ml (about 20--90 microM), MTM repressed MDR1 gene transcription of SBC-3/ADM, a MDR-phenotype subline derived from human small cell lung tumor. Under the same conditions, another aureolic acid, chromomycin A3, showed potent cytotoxicity. FACS analysis revealed that 5 microm MTM depleted the P-glycoprotein (Pgp) and lowered the efflux activity of SBC-3/ADM cells. Furthermore, MTM sensitized the cells against adriamycin. These results suggest that MTM would be a useful modulator of MDR induced by Pgp.
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PMID:Mithramycin represses MDR1 gene expression in vitro, modulating multidrug resistance. 1096 97


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