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

---

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

Cervical cancer patients have a defective immune system. There is a decrease of total white blood cell count including lymphocytes and natural killer (NK) cells. NK cells, one type of lymphocytes, play a role to eliminate cancer cells by antibody dependent cell mediated cytotoxicity (ADCC) mechanism. Previous studies have shown that P-glycoprotein (170 kDa, transmembrane protein) may be a transporter for cytokine releasing in ADCC mechanism. This study proposed to explore the role of bitter melon intake in cervical cancer patients undergoing normal treatment (radiotherapy). Subjects were divided into three groups: 1) normal control (women 35-55 years, n = 35), 2) patient control (n = 30) and 3) patient treatment (n = 30) groups. Patient control and patient treatment groups were cervical cancer patients (stage II or III) treated with radiotherapy (without or with bitter melon ingestion). Blood samples of patient control and patient treatment groups were analyzed for NK cells percentage and P-glycoprotein level. Bitter melon is a Thai herb. Previous studies have shown that bitter melon can stimulate lymphocyte activity in vitro and in vivo (mouse). The authors hope that bitter melon could stimulate the increase of NK cells percentage and P-glycoprotein level on the membrane in blood samples from cervical cancer patients who ingest bitter melon. The results showed an increased percentage of NK cells in patient control and patient treatment groups. The increase in each group is significant (p < 0.05) when compared with the percentage of NK cells from second and third blood sampling time (after radiation with of without bitter melon intake for 45 and 90 days) with first blood sampling time (before treatment). The results also show a significant decrease of P-glycoprotein level (p < 0.05) in second and third blood sampling times when compared with first blood sampling time of the patient treatment group. There was no significant difference of P-glycoprotein (P-gp) level from first, second and third blood sampling times in patient control group. Bitter melon ingestion did not affect NK cell level but it affected the decrease of P-gp level on NK cell membrane.
...
PMID:Effect of bitter melon (Momordica charantia Linn) on level and function of natural killer cells in cervical cancer patients with radiotherapy. 1267 40

Drug cerebral pharmacokinetics may be altered in the case of inflammatory diseases. This may be due to a modification of drug transport through the blood-brain barrier, in particular through drug interaction with the membrane efflux transporter, P-glycoprotein. The objective of this study was to investigate the influence of the inflammatory cytokine, tumor necrosis factor (TNF)-alpha, on the functionality and expression of P-glycoprotein, and on mdr1a and mdr1b mRNA expression in immortalised rat brain endothelial cells, GPNT. Cells were treated with TNF-alpha for 4 days. Levels of mdr1a and mdr1b mRNAs were quantitated using real-time RT-PCR analysis and expression of P-glycoprotein was analyzed by Western blot. The functionality of P-glycoprotein was studied by following the accumulation of [3H]vinblastine in the cells without and with a pre-treatment with a P-glycoprotein inhibitor, GF120918. TNF-alpha increased the levels of mdr1a and mdr1b mRNAs while no effect was observed on protein expression. TNF-alpha increased [3H]vinblastine accumulation indicating a time and concentration-dependent decrease of P-glycoprotein activity. This effect was eliminated when the cells were pre-treated with GF120918. Our observation of a decrease in P-glycoprotein activity could suggest that in the case of inflammatory diseases, brain delivery of P-glycoprotein-dependent drugs can be enhanced.
...
PMID:Influence of tumor necrosis factor-alpha on the expression and function of P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT. 1290 22

P-glycoprotein (P-gp) is an efflux transporter with a wide substrate specificity that plays an important role in the disposition of drugs in the epithelial cells of various tissues, such as the gastrointestinal tract, liver, and kidney. One characteristic feature of this efflux transporter is that its expression and activity are modulated by various factors, including cytokines. Here, we investigated the effect of interferon-gamma (IFN-gamma) on the transport activity of P-gp and its expression in mice, since the cytokine is induced by various stimuli and capable of provoking a variety of cellular responses. Twenty-four hours after a single intraperitoneal injection of IFN-gamma (1 x 10(5) U), mice were intravenously injected with [3H]digoxin, a P-gp substrate, and its pharmacokinetics was examined. IFN-gamma pretreatment resulted in retardation of plasma elimination of the drug with a concomitant increase of its tissue levels in liver, kidney, and intestine. Furthermore, the excretion of [3H]digoxin into the urine and bile, but not into the intestinal lumen, was significantly reduced: the urinary and biliary excretion clearances in IFN-gamma-treated mice were 65 and 55%, respectively, of those clearances in untreated mice. However, the P-gp expression levels were only slightly reduced (20-30% reduction) by IFN-gamma treatment in the liver, kidney, or intestine on Western blot analysis. IFN-gamma also caused a slight down-regulation (20-30% reduction) in the expression of cytochrome P450 3A (CYP3A) on Western blot analysis. Thus, a more pronounced effect may be elicited by IFN-gamma for common substrates of P-gp and CYP3A.
...
PMID:Effect of interferon-gamma on the pharmacokinetics of digoxin, a P-glycoprotein substrate, intravenously injected into the mouse. 1456 74

The aim of this review is to analyse critically the recent literature on the clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplant recipients. Dosage and target concentration recommendations for tacrolimus vary from centre to centre, and large pharmacokinetic variability makes it difficult to predict what concentration will be achieved with a particular dose or dosage change. Therapeutic ranges have not been based on statistical approaches. The majority of pharmacokinetic studies have involved intense blood sampling in small homogeneous groups in the immediate post-transplant period. Most have used nonspecific immunoassays and provide little information on pharmacokinetic variability. Demographic investigations seeking correlations between pharmacokinetic parameters and patient factors have generally looked at one covariate at a time and have involved small patient numbers. Factors reported to influence the pharmacokinetics of tacrolimus include the patient group studied, hepatic dysfunction, hepatitis C status, time after transplantation, patient age, donor liver characteristics, recipient race, haematocrit and albumin concentrations, diurnal rhythm, food administration, corticosteroid dosage, diarrhoea and cytochrome P450 (CYP) isoenzyme and P-glycoprotein expression. Population analyses are adding to our understanding of the pharmacokinetics of tacrolimus, but such investigations are still in their infancy. A significant proportion of model variability remains unexplained. Population modelling and Bayesian forecasting may be improved if CYP isoenzymes and/or P-glycoprotein expression could be considered as covariates. Reports have been conflicting as to whether low tacrolimus trough concentrations are related to rejection. Several studies have demonstrated a correlation between high trough concentrations and toxicity, particularly nephrotoxicity. The best predictor of pharmacological effect may be drug concentrations in the transplanted organ itself. Researchers have started to question current reliance on trough measurement during therapeutic drug monitoring, with instances of toxicity and rejection occurring when trough concentrations are within 'acceptable' ranges. The correlation between blood concentration and drug exposure can be improved by use of non-trough timepoints. However, controversy exists as to whether this will provide any great benefit, given the added complexity in monitoring. Investigators are now attempting to quantify the pharmacological effects of tacrolimus on immune cells through assays that measure in vivo calcineurin inhibition and markers of immunosuppression such as cytokine concentration. To date, no studies have correlated pharmacodynamic marker assay results with immunosuppressive efficacy, as determined by allograft outcome, or investigated the relationship between calcineurin inhibition and drug adverse effects. Little is known about the magnitude of the pharmacodynamic variability of tacrolimus.
...
PMID:Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. 1524 95

P-glycoprotein (P-gp), an ATP-dependent membrane pump encoded by mdr, plays, in addition to its ability to efflux toxins, a role in the resistance to pathogens. We employed mdr1a gene knock out (mdr1a-/-) mice and ectromelia virus (EV) to elucidate the role of P-gp in resistance to EV. Mdr1a-/- mice are more susceptible to EV infection than wild type (wt) mice, showing increased mortality and morbidity. Unexpectedly, virus titres in liver, and in vitro in macrophages and splenocytes were significantly lower in the more susceptible mdr1a-/- mice than wt littermates. Analysis of immunological mechanisms known to influence resistance to EV infection, such as NK and cytotoxic T cell responses, EV specific antibody and cytokine levels did not reveal significant differences between the two strains of mice. Only dendritic cells from mdr1a-/- mice showed impaired migration to the draining lymph nodes compared to wt mice. Our data show that P-gp plays an important role in EV infection by as yet undefined mechanisms.
...
PMID:The multidrug resistance gene mdr1a influences resistance to ectromelia virus infection by mechanisms other than conventional immunity. 1547 31

Patients with refractory inflammatory bowel disease (IBD) exhibit increased expression of intestinal P-glycoprotein (P-gp) as well as elevated luminal IFN-gamma and nitric oxide (NO) levels. Using the in vitro Caco-2 cell culture model, we investigated whether these pathological mediators associated with the etiology of IBD affect functional activity of intestinal efflux systems. IFN-gamma reduced cellular uptake of cyclosporin A (CysA) but not methotrexate (MTX) in a time- and concentration-dependent manner. Simultaneously, P-gp expression increased by approximately twofold. Coincubation with the inducible NO synthase inhibitor l-N(6)-(1-iminoethyl)lysine (l-NIL) dramatically reduced production of intracellular NO in response to IFN-gamma stimulus. The presence of l-NIL also abrogated the cytokine-mediated increase in P-gp expression and function suggesting that NO is required for IFN-gamma-mediated activation of this efflux system. Exposure of Caco-2 cells to the chemical NO donor S-nitroso-N-acetylpenicillamine (SNAP) produced a concentration-dependent decrease in intracellular CysA accumulation that was paralleled by an increase in P-gp expression. Both IFN-gamma and SNAP enhanced DNA binding of NF-kappaB, whereas inclusion of l-NIL dramatically decreased this cytokine-induced effect on NF-kappaB binding. These results suggest that NO mediates IFN-gamma-induced increase in expression and function of intestinal P-gp in the human Caco-2 cell culture model by altering DNA binding of NF-kappaB, which may enhance transcription of the ABCB1 gene encoding for this efflux system.
...
PMID:Nitric oxide mediates increased P-glycoprotein activity in interferon-{gamma}-stimulated human intestinal cells. 1548 47

We report here that beta-galactoside binding protein (betaGBP), an antiproliferative cytokine which can program cancer cells to undergo apoptosis, exhibits equal therapeutic efficacy against cancer cells that display diverse mechanisms of drug resistance and against their parental cells. The mechanisms of drug resistance in the cancer cells that we have examined include overexpression of P-glycoprotein, increased efficiency of DNA repair, and altered expression and mutation in the topoisomerase I and II enzymes. We also report that betaGBP exerted its effect by arresting the cells in S phase prior to the activation of programmed cell death. The uniquely similar profile of response to betaGBP by these drug-resistant cells and their parental cells extends the therapeutic potential of this cytokine in the treatment of cancers and offers a promising alternative to patients whose tumors are refractory to the currently available cadre of chemotherapeutic agents.
...
PMID:Circumventing multidrug resistance in cancer by beta-galactoside binding protein, an antiproliferative cytokine. 1575 55

Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective of this study was to evaluate the risk factors, including human multidrug resistance gene (MDR1), cytochrome P4503A5 (CYP3A5) and cytokine gene polymorphisms, associated with acute persistent rejection (APR) in lung transplant patients. One hundred and twenty-five adult lung transplant patients were studied. MDR1 G2677T, C3435T and CYP3A5 polymorphisms were assessed by direct sequencing of the polymorphic region in patient DNA. Cytokine genotyping for five cytokines was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) technique. Multivariate regression analysis was used to identify the predictors of acute persistent rejection. The dependent variable was the presence or absence of acute persistent rejection based on lung biopsies during the first postoperative year. The independent variables were MDR1 G2677T and C3435T, CYP4503A5 and cytokine polymorphisms, survival status, age, gender, survival days and HLA mismatches. The MDR1 C3435T polymorphism and age were independently associated with acute persistent rejection (p = 0.025, odds ratio = 0.29, 95% CI 0.1-0.86 and p = 0.016, odds ratio = 0.94, 95% CI 0.89-0.98, respectively). For the MDR1 C3435T polymorphism, 72% of patients with the C allele had acute persistent rejection in comparison to 52% for TT patients (p = 0.04). For age, a significant difference was found between the nonrejection group and the rejection group (mean+/-S.D. 52.1+/-11.2 vs. 44.4+/-12.3, p = 0.01). This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The major predictor of acute persistent rejection in the first postoperative year for lung transplant patients was the MDR1 C3435T genotype. This association could be due to drug resistance, altered drug disposition or other immunologic effects associated with P-glycoprotein (P-gp) function. Future prospective treatment algorithms should be developed that will incorporate the knowledge of gene polymorphisms into treatment regimens to improve the outcome following lung transplantation.
...
PMID:The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients. 1581 80

P-glycoprotein (P-gp), a product of the MDR1 gene, is an important factor in the turnover of many drugs and xenobiotics. Recent reports have suggested that P-gp can also be involved in the transport of cytokines. The aim of this study was to examine the role of P-gp in cytokine release from phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (MNCs) as well as in the release of cytokines from MNCs treated with methotrexate (MTX) and dexamethasone (DEX). The study was carried out on PHA-stimulated MNC from 10 healthy subjects. Flow cytometry was applied to measure interleukin (IL)-2, IL-4, IL-6, IL-10, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha levels in the culture supernatants. In the experiments verapamil (VER) and P-gp specific monoclonal antibodies (mAb) (clone 17F9) were used to inhibit P-gp function. P-gp inhibitors suppressed the release of IL-2, IL-4, IFN-gamma and TNF-alpha from PHA-stimulated MNC, whereas release of IL-6 and IL-10 remained unaffected. VER and mAb significantly decreased the release of IL-2, IL-4, TNF-alpha and INF-gamma in MNC cultures treated with MTX or DEX. The results of this study suggest that P-gp may be involved in the transmembrane transport of some cytokines. Moreover, it seems that blocking of P-gp function may influence the release of some cytokines from MNCs, displaying an additive inhibitory effect to DEX and MTX.
...
PMID:Involvement of P-glycoprotein in the release of cytokines from peripheral blood mononuclear cells treated with methotrexate and dexamethasone. 1625 74

At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ET(B) receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), activated a TNF-R1 receptor, released ET-1, activated ET(B) receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced P-glycoprotein activity through TNF-alpha release, ET-1 release, and ET(B) receptor signaling. TNF-alpha and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy.
...
PMID:Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide. 1627 73


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---