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)

Multidrug resistance (MDR) is the phenomenon in which cultured tumor cells, selected for resistance to one chemotherapeutic agent, simultaneously acquire resistance to several apparently unrelated drugs. The MDR phenotype is multifactorial. The best-studied mechanism involves the expression of a membrane protein that acts as an energy-dependent efflux pump, known as P-glycoprotein (Pgp), capable of extruding toxic materials from the cell. In this work, resistance to UVA radiation, but not to UVC nor UVB, was observed in an MDR leukemia cell line. This cell line overexpresses Pgp. To study the role of Pgp in the resistance to UVA radiation, two MDR modulators or reversing agents (verapamil and cyclosporin A) capable of blocking Pgp activity were used. Cell viability was assessed and the techniques of flow cytometry and fluorescence microscopy were employed to measure the extrusion of rhodamine 123 by the efflux pump. The results show that MDR modulators did not modify the resistance to UVA radiation. Furthermore, although cell viability was not significantly altered, Pgp function was impaired after UVA treatment, suggesting that this glycoprotein may be a physical target for oxidative damage, and that other factors may be responsible for the UVA resistance. In agreement with this, it was found that the resistant cell line presented a higher catalase activity than the parental (non-MDR) cell line.
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PMID:Differences in sensitivity to UVC, UVB and UVA radiation of a multidrug-resistant cell line overexpressing P-glycoprotein. 1037 8

The resistance to cytotoxic drugs represents a major obstacle to successful cancer therapy. The intrinsic resistance of tumoral cells is one of major causes of treatment failure. The overexpression of a membrane associated glycoprotein, P-glycoprotein, in tumoral cell lines, resistant to a wide range of drugs, permitted the description of a multidrug resistance (MDR) phenotype. This P-glycoprotein, which appears to play a role in drug efflux is encoded by the mdr1 gene in humans. The frequent mdr1 gene overexpression in clinically resistant tumours suggest that this gene may be the cause of treatment failure in human cancer. This review summarizes recent developments in this area, which suggest that both the activity of the pump and its genetic regulation are potential targets for new anticancer therapies.
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PMID:[Multidrug or pleiotropic resistance]. 1097 7

The development of multiple drug resistance in tumor cells is a significant problem in cancer therapy. In human, one of the reasons causing the resistance is due to the overexpression of the mdr1 gene product, P-glycoprotein. In our study, we had developed multiple drug resistant HepG2 cell line (HepG2/DR). To reverse the resistance, HepG2-DR cells were treated with antisense RNA against mdr1 gene. Total RNA and protein were extracted from the transfected cells. Northern analysis showed that mRNA level of mdr1 was decreased whereas a reduction in P-glycoprotein was detected by Western blot. By using flow cytometry, the ability of intracellular doxorubicin retention increased and drug efflux decreased in the treated cells. The result also showed that the cellular sensitivity to doxorubicin, vincristine and methotrexate measured in IC50 increased 83.3% 84.6% and 50% respectively. All these findings suggested that the expression of p-glycoprotein was successfully inhibited by antisense RNA and the drug resistance was reduced.
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PMID:Inhibition of P-glycoprotein expression and reversal of drug resistance of human hepatoma HepG2 cells by multidrug resistance gene (mdr1) antisense RNA. 1105 61

The Dubin-Johnson syndrome is an inherited disorder characterized by conjugated hyperbilirubinemia. The deficient hepatobiliary transport of anionic conjugates is caused by the absence of a functional multidrug-resistance protein 2 (MRP2, symbol ABCC2) from the apical (canalicular) membrane of hepatocytes. Mechanisms underlying this deficiency may include rapid degradation of mutated MRP2 messenger RNA (mRNA) or impaired MRP2 protein maturation and trafficking. We investigated the consequences of the mutation MRP2Delta(R,M), which leads to the loss of 2 amino acids from the second ATP-binding domain of MRP2. The MRP2Delta(R,M) mutation is associated with the absence of the MRP2 glycoprotein from the apical membrane of hepatocytes. Transfection of mutated MRP2 complementary DNA (cDNA) led to an MRP2Delta(R,M) protein that was only core glycosylated, sensitive to endoglycosidase H digestion, and located in the endoplasmic reticulum (ER) of transfected HEK293 and HepG2 cells. This indicated that deletion of Arg1392 and Met1393 leads to impaired maturation and trafficking of the protein from the ER to the Golgi complex. Inhibition of proteasome function resulted in a paranuclear accumulation of the MRP2Delta(R,M) protein, suggesting that proteasomes are involved in the degradation of the mutant protein. This is the first mutation in Dubin-Johnson syndrome shown to cause deficient MRP2 maturation and impaired sorting of this glycoprotein to the apical membrane.
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PMID:Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. 1109 39

The effect of P-glycoprotein inhibition on the uptake of the HIV type 1 protease inhibitor saquinavir into brain capillary endothelial cells was studied using porcine primary brain capillary endothelial cell monolayers as an in vitro test system. As confirmed by polymerase chain reaction and Western blot analysis, this system functionally expressed class I P-glycoprotein (pgp1A). P-Glycoprotein isoforms pgp1B or pgp1D could not be detected. The uptake of saquinavir into endothelial cells could be described as the result of a diffusional term of uptake and an oppositely directed saturable extrusion process. Net uptake of saquinavir into cultured brain endothelial cells could be increased significantly up to 2-fold by SDZ PSC 833 in a dose-dependent manner, with an IC(50) of 1.13 microM. In addition, the HIV protease inhibitor ritonavir inhibited p-glycoprotein-mediated extrusion of saquinavir with an IC(50) of 0.2 microM, indicating a high affinity of ritonavir for p-glycoprotein. In conclusion, we showed that the HIV protease inhibitor ritonavir is a more potent inhibitor of P-glycoprotein than the multidrug resistance (MDR)-reversing agent SDZ PSC 833. The inclusion of this drug in combination regimens may greatly facilitate brain uptake of HIV protease inhibitors, which is especially important in patients suffering from AIDS dementia complex.
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PMID:HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. 1123 Aug 2

The inhibition of the Na+/K+-ATPase by cardiotonic drugs like ouabain deeply perturbs both the properties of the cell membrane and the ionic composition of the cytoplasm and hence alters fundamental cell reactions. These three types of reactions may be involved in the stimulation of multidrug resistance 1 (MDR-1) gene expression and the synthesis of permeability glycoprotein [P-glycoprotein (P-gp)]. We have determined whether ouabain, which binds to an extracellular motif of the Na+/K+-ATPase, stimulates MDR-1 gene expression by measuring both mRNA and protein and whether the resulting P-gp extrudes hydrophobic compounds and causes resistance to antimitotic agents. The experiments were performed on Calu-3 cells, a human cell line from a pulmonary carcinoma. Northern blotting showed that treating the cells with submicromolar concentrations of ouabain stimulated MDR-1 gene expression within 24 h. The ouabain-induced stimulation of MDR-1 expression was not restricted to Calu-3 cells but also occurred in human carcinomatous colon (T-84 and HT-29) and hepatic (H7V3) cells. However, it is not ubiquitous because it was not found in HeLa cells. The stimulation was reproduced by other Na+/K+-ATPase inhibitors and occurred via enhanced gene transcription, apparently due to the increased cytosolic calcium concentration. Ouabain also increased the membrane content of P-gp, as detected by immunoblotting and immunohistology. We have developed a microvideo assay based on the properties of acetoxymethyl ester calcein and calcein to show that this P-gp extruded the hydrophobic acetoxymethyl ester calcein. Ouabain also caused the Calu-3 cells to become resistant to doxorubicin and vinblastine. Thus, although ouabain acts extracellularly, it may stimulate MDR-1 gene expression and P-gp synthesis and make cells resistant to hydrophobic cytotoxic compounds.
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PMID:Drug resistance induced by ouabain via the stimulation of MDR1 gene expression in human carcinomatous pulmonary cells. 1124 85

Chronic myeloid leukaemia (CML) is characterized by marked expansion of the myeloid series, and is thought to arise as a direct result of the bcr-abl fusion-gene. The BCR-ABL oncoprotein is a constitutively active protein tyrosine kinase (PTK), which results in altered cell signalling and is responsible for the changes that characterize the malignant cells of CML. It has been shown that the increased tyrosine kinase activity of BCR-ABL is a requirement for transformation and is, therefore, a legitimate target for pharmacological inhibition. Several compounds have now been identified as relatively selective inhibitors of BCR-ABL, including members of the tyrphostin family, herbimycin A and most importantly the 2-phenylaminopyrimidine ST1571. Having established the efficacy of this agent in vitro, phase I trials using an oral formulation were commenced in the USA in mid 1998. Early data from an interferon-alpha (IFN) resistant/refractory or intolerant cohort demonstrated good patient tolerance and effective haematological control at doses above 300 mg. More promising was its ability to induce cytogenetic responses in this pretreated group of patients. Phase II data, albeit far from complete, appear to confirm its efficacy even in the context of advanced disease and phase III clinical trials are currently underway in many countries. Recent laboratory evidence, however, suggests that the development of drug resistance is a possibility (via amplification of the bcr-abl fusion gene, overexpression of P-glycoprotein or binding of ST1571 to alpha1 acid glycoprotein) and that combination therapy including ST1571 should be considered.
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PMID:Tyrosine kinase inhibitors in the treatment of chronic myeloid leukaemia: so far so good? 1140 8

The absorption of many drugs is affected by their interaction with ATP-binding cassette (ABC) transporters. The most extensively studied of these ABC transporters is the proein product of MDR1 (multidrug resistance) that encodes a 170-kDa integral plasma membrane phosphorylated glycoprotein known as P-glycoprotein (P-gp). The purpose of this study was to determine, using two different methods, whether the nonsedating antihistamine loratadine (L) and its active metabolite desloratadine (DL) interact with P-gp. MDR cells presenting human P-gp were incubated with the fluorescent P-gp substrate daunorubicin with or without L, DL, and several positive controls. The IC(50) of loratadine (approximately 11 microM) was approximately 160 times the maximum observed plasma concentration (C(max)) following a dose of 10 mg. The IC(50) of desloratadine (approximately 43 microM) was approximately 880 times the C(max) following a dose of 5 mg. The positive control, cyclosporin A, had an IC(50) of approximately 1 microM. ATP hydrolysis activity was measured in the membrane fraction prepared from MDR cells presenting P-gp, which were exposed to various concentrations of test compounds. Known substrates of P-gp demonstrated clear, repeatable, concentration-dependent increases in ATP hydrolysis activity. L caused an increase in ATPase activity above basal levels. L had a V(max) about 200% basal activity and K(m) of approximately 3 microM for P-gp. In contrast, DL had no significant effect on baseline ATP hydrolysis. L inhibited human P-gp much less than verapamil or cyclosporin A. DL inhibited human P-gp significantly less than L (4 times). DL therefore is not a significant inhibitor of P-gp and should not cause clinical drug interactions with agents that are P-gp substrates.
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PMID:Evaluation of the interaction of loratadine and desloratadine with P-glycoprotein. 1145 24

We investigated the expression and function of mdr1a p-glycoprotein in peripheral nerves, including the VIIth and VIIIth nerves, using mdr1a p-glycoprotein gene knockout mice [mdr1a(-/-) mice] and wild-type mdr1a(+/+) mice. P-glycoprotein expression in capillary endothelial cells of the peripheral nerve tissues was detected by immunohistochemical and RT-PCR analyses in mdr1a(+/+) mice but not in mdr1a(-/-) mice. Pharmacokinetic analyses indicated that, compared to mdr1a(+/+) mice, mdr1a(-/-) mice showed a significantly higher accumulation of p-glycoprotein substrate drugs such as vinblastine and doxorubicin, which are neurotoxic. Tissue concentrations of vinblastine and doxorubicin were lower in the order of the brain, peripheral nerves and most other organs. However, increased accumulation was not detected after administering another neurotoxic drug, cisplatin, indicating that p-glycoprotein is selective at extruding drugs. These data indicate that mdr1a p-glycoprotein, which acts as an efflux pump, might play an important role in the blood-nerve barrier to prevent side effects induced by neurotoxic p-glycoprotein substrate drugs. The participation of p-glycoprotein in the blood-nerve barrier is considered to represent a new functional mechanism of this barrier.
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PMID:Homozygous disruption of the mdrla P-glycoprotein gene affects blood-nerve barrier function in mice administered with neurotoxic drugs. 1167 73

Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at http://www.med.rug.nl/mdl/humanabc.htm and http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html. A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear.
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PMID:Resistant mechanisms of anthracyclines--pirarubicin might partly break through the P-glycoprotein-mediated drug-resistance of human breast cancer tissues. 1179 Nov 27


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