Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to characterize two cis-diamminedichloroplatinum(II) (CDDP) resistant cell lines established from human larynx carcinoma HEp2 cells through repeated treatments with increased CDDP concentrations. CK2 cells obtained by continuous treatments were more resistant to CDDP than CA3 cells obtained by acute treatments. The examination of growth characteristics showed that both CDDP resistant cells had doubling times identical to that of the parental cells, but had lower plating efficiency. The possible involvement of glutathione (GSH), glutathione transferases (GST), metallothioneins, P-glycoprotein and drug accumulation in CDDP resistance was examined. Glutathione contents were elevated in both CDDP resistant lines. However, neither GSH nor GST were involved in CDDP resistance. This was demonstrated by simultaneous incubation of parental and CDDP resistant cells with CDDP and specific inhibitors of GSH and GST alpha and pi (buthionine sulfoximine and ethacrinic acid). Similarly, verapamil, an inhibitor of P-glycoprotein, did not influence the sensitivity of parental and resistant cells to CDDP. As compared to the parental cells, CK2 cells became resistant and CA3 cells became sensitive to cadmium, indicating increased level of metallothioneins in CK2 cells, and reduced level in CA3 cells. Measurements of platinum contents in parental and CDDP resistant cells after 1, 3 and 6 hours exposure to 70 mumol CDDP showed reduction in platinum accumulation after each exposure time in CK2 cells, and after 6 hours exposure in CA3 cells. This study identified decreased platinum accumulation as an important mechanism of CDDP resistance in human larynx carcinoma cells.
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PMID:Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): mechanisms involved in the resistance. 793 85

In our previous study we developed two lines of human larynx carcinoma HEp2 cells resistant to cis-diamminedichloroplatinum(II) (CDDP) due to acute (CA3 cells), or continuous (CK2 cells) treatments with increased CDDP concentrations. CA3 line was 2.3-fold resistant, and CK2 line 3.7-fold resistant to CDDP as compared to the parental cells. In this study the sensitivity of CDDP resistant and parental cells to several antitumor drugs was examined using clonogenic survival assay. CK2 cells were 1.7-fold more resistant to vincristine than parental cells, while CA3 cells exhibited resistance to vincristine only at higher concentrations of this drug. Verapamil, an inhibitor of P-glycoprotein, was not able to reverse the resistance of CK2 cells to vincristine, indicating that this cross-resistance did not involve P-glycoprotein. As compared to the parental cells, CK2 cells were 2.1-fold resistant, and CA3 cells 1.7-fold resistant to mitomycin C. CK2 cells were 2-fold more resistant to 5-fluorouracil than the parental cells, while CA3 cells did not exhibit any change in the sensitivity to this drug. CA3 cells were 0.4-fold sensitive to epoxide and 0.53-fold sensitive to doxorubicin, while CK2 cells had the same sensitivity to these drugs as the parental cells. Our results showed that treatment schedule determines the response of CDDP resistant human larynx carcinoma cells to additional drugs, suggesting the complexity of the judicious choice of the drugs in the combined modality treatments of cancer.
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PMID:Human larynx carcinoma cells resistant to cis-diamminedichloroplatinum(II): cross-resistance patterns. 793 86

Previously, the abermectin-induced neurotoxicity of subpopulation of CF-1 mice was shown to be caused by the deficiency of mdr-3 P-glycoprotein. Here, we have characterized the molecular nature of the mdr-3 gene mutation in this subpopulation of CF-1 mice. The size of mdr-3 mRNA transcript from ivermectin-sensitive mutant mice was different from that of wild-type mice. Sequence analysis of RT-PCR products isolated from the mutant brain disclosed that the exon 23 of the mdr-3 gene is deleted or altered in the transcripts. The analysis of the genomic locus revealed an insertion of a solo long terminal repeat (LTR) of the ecotropic murine leukemia virus in the reverse orientation in the intron of the mdr-3 gene, causing abnormal splicing and thereby disrupting the mdr-3 gene function. In addition, histopathological analysis of the brains of the ivermectin-treated mutants revealed selective neuronal degeneration in the hippocampal CA3 region. This is the first reported case of a gene mutation induced by a solo retroviral LTR with a phenotypic consequence in the mouse, and may provide new insights into the understanding of the effects of viral solo LTR sequences on mammalian gene expression.
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PMID:Insertion of a retroviral solo long terminal repeat in mdr-3 locus disrupts mRNA splicing in mice. 1100 97

Several recent studies have shown that the multidrug transporter P-glycoprotein (PGP) is over-expressed in endothelial cells from brain blood vessels of patients with refractory temporal lobe epilepsy (TLE), suggesting that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). Furthermore, over-expression of PGP has been found in astrocytes of epileptogenic tissue. However, it is not known in which regions of the temporal lobe PGP over-expression occurs and whether the over-expression is a result of uncontrolled seizures, of the mechanisms underlying epilepsy, or of chronic administration of AEDs. In the present study, we used the rat kainate model of TLE to study the time-course of PGP expression in capillary endothelium and parenchyma of the hippocampus and several other limbic brain regions thought to be involved in TLE. Kainate was administered at a dose which produced a generalized convulsive status epilepticus (SE), which was limited to a duration of 90 min by diazepam. PGP was detected by immunohistochemistry either 24 h or 10 days after SE, using a monoclonal PGP antibody. In both kainate-treated rats and controls, PGP staining was observed mainly in microvessel endothelial cells and, to a much lesser extent, in parenchymal cells. Twenty-four hours after SE, significant increases in PGP expression were determined in endothelial cells of the dentate gyrus and in parenchymal cells of the CA1 and CA3 sectors of the hippocampus. Furthermore, increased PGP expression was observed in the amygdala, piriform, and parietal cortex, but not in the substantia nigra. Ten days after the kainate-induced SE, except for an increase in parenchymal PGP expression in the dentate hilus and CA1 sector, no significant differences to controls were determined, indicating that most PGP increases seen 24 h after SE were only transient. The data indicate that PGP over-expression is a transient result of seizures and occurs in several regions of the temporal lobe. Seizure-induced over-expression of PGP in capillary endothelial cells of the BBB is likely to reduce the penetration of AEDs into brain parenchyma, which could explain the drug-refractoriness of seizures in TLE.
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PMID:Transient increase of P-glycoprotein expression in endothelium and parenchyma of limbic brain regions in the kainate model of temporal lobe epilepsy. 1239 76

Increased expression of the multidrug transporter P-glycoprotein (Pgp; ABCB1) has previously been found in epileptogenic brain tissue from patients with pharmacoresistant temporal lobe epilepsy (TLE) as well as in the hippocampus and other limbic brain regions in the rat kainate model of TLE. Approaches to the quantification of Pgp expression have mainly been based on subjective visual estimation of the level of Pgp immunoreactivity in brain sections. In the present study, computer-assisted image analysis based on optical density (OD) measurements was used to examine immunohistochemical expression of Pgp in the kindling model of TLE. Sections from kainate-treated rats were used for comparison. Using diaminobenzidine as chromogen, Pgp was exclusively located in brain capillary endothelial cells, which was confirmed by double-labeling with an antibody against the endothelial glucose transporter (GLUT-1). After kainate-induced seizures, the intensity of endothelial Pgp staining significantly increased by 70-80% in the dentate gyrus. A significant, albeit less marked increase in Pgp expression in this area was also seen after amygdala-kindled seizures. Furthermore, Pgp was upregulated after kindling in the hilus of the dentate gyrus, the CA1 and CA3 sectors of the hippocampus, and the piriform and cerebral cortex. In kindled rats, most Pgp alterations occurred ipsilateral to the electrode in the basolateral amygdala. The data demonstrate that computer-assisted image analysis using OD is an accurate and rapid method to determine the relative amount of Pgp protein in brain sections and the effects of seizures on this multidrug transporter. The fact that Pgp overexpression in brain capillary endothelial cells occurs in two established models of difficult-to-treat TLE substantiates the notion that seizure-induced upregulation of Pgp contributes to multidrug resistance (MDR) in epilepsy.
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PMID:Increased expression of the multidrug transporter P-glycoprotein in limbic brain regions after amygdala-kindled seizures in rats. 1506 76

P-glycoprotein (P-gp) is an ABC transporter expressed at the blood brain barrier and regulates the brain uptake of various xenobiotics and endogenous mediators including glucocorticoid hormones which are critically important to the stress response. Moreover, P-gp is expressed on microglia, the brain's immune cells, which are activated by stressors and have an emerging role in psychiatric disorders. We therefore hypothesised that germline P-gp deletion in mice might alter the behavioral and microglial response to stressors. Female P-gp knockout mice displayed an unusual, frantic anxiety response to intraperitoneal injection stress in the light-dark test. They also tended to display reduced conditioned fear responses compared to wild-type (WT) mice in a paradigm where a single electric foot-shock stressor was paired to a context. Foot-shock stress reduced social interaction and decreased microglia cell density in the amygdala which was not varied by P-gp genotype. Independently of stressor exposure, female P-gp deficient mice displayed increased depression-like behavior, idiosyncratic darting behavior, age-related social withdrawal and hyperactivity, facilitated sensorimotor gating and altered startle reactivity. In addition, P-gp deletion increased microglia cell density in the CA3 region of the hippocampus, and the microglial cells exhibited a reactive, hypo-ramified morphology. Further, female P-gp KO mice displayed increased glucocorticoid receptor (GR) expression in the hippocampus. In conclusion, this research shows that germline P-gp deletion affected various behaviors of relevance to psychiatric conditions, and that altered microglial cell activity and enhanced GR expression in the hippocampus may play a role in mediating these behaviors.
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PMID:Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice. 2850 79