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)

P-glycoprotein expression in lymphoid malignancies has the potential to compromise the efficacy of many therapeutic regimens using anthracyclines, glucocorticoids, and Vinca alkaloids. All three classes of drugs are transported by P-glycoproteins. We have explored the possibility that modified steroids could serve a dual purpose, as glucocorticoid receptor agonists and P-glycoprotein inhibitors. Substitution of such steroids for those currently in use would help to overcome the selective advantage held by cells expressing P-glycoproteins. 17-Deoxydexamethasone and dichlorisone were modified by the addition of a dimethylamino benzoate group at the 21-carbon atom of the steroids. The two resulting steroids, SA47 and SA450, were potent glucocorticoid receptor agonists also capable of inhibiting the human P-glycoprotein with an efficiency equal to that of verapamil. Thus, both compounds are examples of steroids that could potentially serve as beneficial substitutions for dexamethasone or prednisolone in the chemotherapy of lymphomas and leukemias.
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PMID:Chemosensitizing steroids: glucocorticoid receptor agonists capable of inhibiting P-glycoprotein function. 904 51

Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-transporting P-glycoprotein product from the blood-brain barrier on the distribution and cell nuclear uptake of [3H]-dexamethasone in the brain. [3H]-dexamethasone (4 microg/kg mouse) was administered s.c. to adrenalectomized mdr1a (-/-) and mdr1a (+/+) mice. One hour later, the mice were decapitated, and the radioactivity was measured in homogenates of cerebellum, blood, and liver following extraction of the radioactive steroid. The frontal brain was cut in sections for autoradiography. In the cerebellum of the mdr1a mutants, the amount of [3H]-dexamethasone relative to blood was about 5-fold higher than observed in the controls, whereas the ratio in blood vs. liver was not different. Using autoradiography, it was found that brain areas expressing the glucocorticoid receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in cell nuclear uptake of radiolabeled steroid. The amount of retained steroid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [3H]-dexamethasone concentration in pituitary was not affected by mdr1a gene disruption. The GR messenger RNA expression pattern in hippocampus was not different between the wild types and mdr1a mutants, which rules out altered receptor expression as a cause of the enhanced dexamethasone uptake. In conclusion, the present study demonstrates that the brain is resistant to penetration by dexamethasone because of mdr1a activity at the level of the blood-brain barrier. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release. Dexamethasone poorly substitutes for depletion of the endogenous glucocorticoid from the brain and therefore, in this tissue, may cause a condition resembling that of adrenalectomy.
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PMID:Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. 952 63

Although the immunosuppressive drugs FK506, rapamycin and cyclosporin A have been reported to potentiate transcriptional activation mediated by a non-saturating concentration of the glucocorticoid receptor agonist dexamethasone, the precise mechanism(s) underlying these responses remains unclear. The murine L-929-derived LMCAT cell line stably transfected with the mouse mammary tumor virus promoter-chloramphenicol acetyl transferase reporter gene construct was utilized in the present study to further investigate the mechanism(s) underlying this dexamethasone potentiation as well as the possible agonist specificity of this potentiation. The present data demonstrate that pretreatment (2 h) of LMCAT cells with 10 microM FK506, rapamycin or cyclosporin A results in the potentiation of reporter gene transcription mediated not only by dexamethasone (approximately 12-fold), but also by hydrocortisone (approximately 6-fold) and triamcinolone acetonide (approximately 2.5-fold). In sharp contrast, the data show for the first time that pretreatment with any one of these immunosuppressive drugs suppresses (approximately 2-8-fold) the transcriptional responses mediated by corticosterone, deoxycorticosterone, and cortexolone. Pretreatment of intact LMCAT cells with FK506 increases the subsequent whole cell specific binding of [3H]dexamethasone, but does not increase specific cytoplasmic binding when the tritiated agonist is added directly to cytosolic extracts prepared from the pretreated cells. These data suggest that the FK506-mediated potentiation of the transcriptional responses induced by some agonists, like dexamethasone, may be related to the ability of this immunosuppressant to inhibit the membrane-associated multidrug resistance (MDR) P-glycoprotein, which actively extrudes some steroids from cells. Identical pretreatment with FK506 has no detectable effect on the subsequent whole cell specific binding of [3H]corticosterone, a steroid which is not effectively extruded by the MDR pump. Two additional MDR pump inhibitors, verapamil and quinidine, potentiate (30-fold) the dexamethasone-mediated transcriptional response as expected, but have no detectable effects on a corticosterone-mediated transcriptional response. Unlike immunosuppressive drugs, these ion channel blockers do not bind to receptor-associated immunophilins (FK506-binding proteins or cyclophilins). Collectively, these results suggest that immunosuppressants potentiate a dexamethasone-mediated transcriptional response in LMCAT cells by inhibiting efflux of this steroid. In contrast, these drugs appear to suppress a corticosterone-mediated transcriptional response by a different mechanism, perhaps one involving their binding to glucocorticoid receptor-associated immunophilins.
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PMID:Agonist-specific modulation of glucocorticoid receptor-mediated transcription by immunosuppressants. 968 11

Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients. Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of rifampicin treatment are a consequence of GR activation.
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PMID:Rifampicin is not an activator of glucocorticoid receptor. 1072 19

The cytokine interleukin-17 may play a role in the recruitment of airway neutrophils, and interleukin-17 protein is increased in the airways of patients with asthma. In this study, we characterised the effect of interleukin-17 on the release of the neutrophil-recruiting cytokines granulocyte chemotactic protein (GCP)-2, growth-related oncogene (GRO)-alpha and interleukin-8 in human bronchial epithelial (HBE) cells. We also characterised the involvement of mitogen-activated protein (MAP) kinases as well as the effect of beta-adrenoceptor and glucocorticoid receptor stimulation and calcineurin and P-glycoprotein inhibition on these epithelial responses to interleukin-17. We found that interleukin-17 (1-1000 ng/ml) increased the release of GCP-2, GRO-alpha and interleukin-8 in a concentration-dependent manner. This interleukin-17-induced release of C-X-C chemokines was sensitive to inhibition of the p38 MAP kinase pathway and to stimulation of glucocorticoid receptors. In contrast, stimulation of beta-adrenoceptors increased the release of interleukin-8 and did not markedly alter the release of GCP-2 and GRO-alpha. Inhibition of calcineurin and of P-glycoproteins did not exert any substantial effect on the release of C-X-C chemokines. In conclusion, interleukin-17 bears the potential to increase neutrophil recruitment into the airways by releasing several, different C-X-C chemokines, including GCP-2, GRO-alpha and interleukin-8 in human bronchial epithelial cells. Inhibition of the p38 MAP kinase pathway and glucocorticoid receptor stimulation constitute two credible therapeutic strategies against this interleukin-17-induced release of neutrophil-recruiting cytokines.
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PMID:Pharmacological modulation of interleukin-17-induced GCP-2-, GRO-alpha- and interleukin-8 release in human bronchial epithelial cells. 1259 Nov 13

1. Incubation of LMCAT fibroblast cells with antidepressants potentiates glucocorticoid receptor (GR)-mediated gene transcription in the presence of dexamethasone and cortisol, but not of corticosterone. We have shown that antidepressants do so by inhibiting the LMCAT cell membrane steroid transporter (which is virtually identical to the multidrug resistance P-glycoprotein) and thus by increasing dexamethasone or cortisol intracellular concentrations. However, previous experiments with the antidepressant fluoxetine in the presence of dexamethasone have produced negative results (Pariante et al. (2001). Br. J. Pharmacol., 134, 1335-1343). 2. We have since re-examined the effects of fluoxetine on GR-mediated gene transcription in the presence of dexamethasone. Moreover, we have examined the effects of fluoxetine on GR-mediated gene transcription in the presence of cortisol and corticosterone, and on the intracellular accumulation of radioactive cortisol and corticosterone. Finally, we have examined the effects of fluoxetine on inhibition of P-glycoprotein activity in Caco-2 cells. 3. We now find that fluoxetine (1-10 micro M) enhances GR-mediated gene transcription in the presence of dexamethasone and cortisol (+140-170%), but not of corticosterone, and increases the intracellular accumulation of (3)H-cortisol (+5-15%), but not of (3)H-corticosterone. Moreover, fluoxetine (10 micro M) induces approximately 30% inhibition of PGP activity in Caco-2 cells. 4. Our results show that fluoxetine, like other antidepressants, inhibits membrane steroid transporters.
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PMID:Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters. 1287 29

Glucocorticoids are potent inhibitors of T cell activation and proinflammatory cytokines and are highly effective treatment for active inflammatory bowel disease (IBD). However, failure to respond, acutely or chronically, to glucocorticoid therapy is a common indication for surgery in IBD, with as many as 50% of patients with Crohn's disease (CD) and approximately 20% of patients with ulcerative colitis (UC) requiring surgery in their lifetime as a result of poor response to glucocorticoids. Studies report that approximately one-third of patients with CD are steroid dependent and one-fifth are steroid resistant while approximately one-quarter of patients with UC are steroid dependent and one-sixth are steroid resistant. While the molecular basis of glucocorticoid resistance has been widely assessed in other inflammatory conditions, the pathophysiology of the glucocorticoid resistance in IBD is poorly understood. Research in IBD suggests that the phenomenon of glucocorticoid resistance is compartmentalised to T-lymphocytes and possibly other target inflammatory cells. This review focuses on three key molecular mechanisms of glucocorticoid resistance in IBD: (i) decreased cytoplasmic glucocorticoid concentration secondary to increased P-glycoprotein-mediated efflux of glucocorticoid from target cells due to overexpression of the multidrug resistance gene (MDR1); (ii) impaired glucocorticoid signaling because of dysfunction at the level of the glucocorticoid receptor; and (iii) constitutive epithelial activation of proinflammatory mediators, including nuclear factor kappa B, resulting in inhibition of glucocorticoid receptor transcriptional activity. In addition, the impact of disease heterogeneity on glucocorticoid responsiveness and recent advances in IBD pharmacogenetics are discussed.
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PMID:Glucocorticoid resistance in inflammatory bowel disease. 1296 27

The aim of this study was to evaluate if the permeability of inhaled corticosteroids entering the brain is reduced and if P-glycoprotein (P-gp) transporters are involved. Currently employed inhaled corticosteroids were given intravenously and intratracheally to rats at a dose of 100 microg kg-1. An ex-vivo receptor binding assay was used to monitor over 12 h the glucocorticoid receptor occupancy in the brain and a systemic reference organ (kidney). The involvement of P-gp in the brain permeability of triamcinolone acetonide was assessed in wild-type mice and mdr1a(-/-) knockout mice (mice lacking the gene for expressing P-gp). After both forms of administration, the average brain receptor occupancies were 20-56% of those of the reference organ, with the more lipophilic drugs showing a more pronounced receptor occupation. While the receptor occupancies in the liver of wild-type and mdr1a(-/-) mice were similar after administration of triamcinolone acetonide, brain receptor occupancies in mdr1a(-/-) mice were significantly greater (mdr1a(-/-): 47.6%, 40.2-55.0%, n=14; 2; wild-type: 11.5+/-33.0%, n=14; 3). Penetration into the brain for inhaled corticosteroids (especially those of lower lipophilicity) is reduced. Experiments in mdr1a(-/-) mice confirmed the involvement of P-gp transporters. Further studies are needed to assess whether potential drug interactions at the transporter level are of pharmacological significance.
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PMID:Brain permeability of inhaled corticosteroids. 1610 36

Exposure of the fetus and placenta to maternal glucocorticoids is normally limited by the placental glucocorticoid barrier, which consists primarily of placental 11beta-hydroxy-steroid dehydrogenase type 2-mediated conversion of cortisol to the biologically inactive cortisone. Studies in the rodent brain show that P-glycoprotein (P-gp) is also an important physiological regulator of glucocorticoid access to the glucocorticoid receptor (GR) in target cells because it exports cortisol back into peripheral circulation against a concentration gradient. Whether P-gp of placental origin also has this capacity is unknown. Therefore, we used the human placental choriocarcinoma cell line BeWo and its daughter cell line, BeWoMDR, virally transduced with P-gp, to assess whether placental P-gp regulates access of glucocorticoids to the GR. Quantitative PCR showed that BeWoMDR cells express approximately 10-fold higher levels of P-gp mRNA than BeWo cells, and syncytialization increased P-gp mRNA by approximately 7-fold. Elevated P-gp expression in BeWoMDR cells reduced activation of the GR by dexamethasone and cortisol (10(-9) to 10(-6) M) to around 40% of that in BeWo cells. Inhibition of P-gp-mediated glucocorticoid efflux by cyclosporin A in BeWoMDR cells returned GR activation to levels similar to those in BeWo cells. Diffusion of dexamethasone across BeWoMDR monolayers occurred at a slower rate than that across BeWo monolayers, but this difference was eliminated by cyclosporin A. These data support the hypothesis that P-gp contributes to the placental glucocorticoid barrier. Thus, 11beta-hydroxysteroid dehydrogenase type 2 and P-gp may act in unison to reduce fetal and placental exposure to maternal glucocorticoids and thereby minimize their growth inhibitory actions.
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PMID:P-glycoprotein restricts access of cortisol and dexamethasone to the glucocorticoid receptor in placental BeWo cells. 1687 36

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis has been found in some psychiatric disorders, especially in older patients with severe depression. Altered feedback inhibition, as demonstrated by increased circulating cortisol and nonsuppresssion of cortisol following administration of dexamethasone, may be to blame. Two glucocorticoid receptors control the HPA axis, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). MR regulates normal HPA fluctuations and the GR regulates in times of stress. Long-term antidepressant treatment in humans has been shown to upregulate both GR and MR in the brain, whereas short-term treatment has been shown to downregulate GR and MR. After 6-9 weeks of treatment GR function returns to normal, and the MR stays upregulated. Chronic antidepressant treatment in rodents has been shown to reduce HPA activity, even in the absence of GR or MR upregulation. These effects of antidepressants on HPA regulation may be attributed in part to regulation of the multidrug resistance protein transporter, P-glycoprotein. Finding relationships between antidepressant action and HPA regulation leads to the conclusion that the disruption of the HPA may be more a contributing factor to depression than other biological abnormalities.
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PMID:The effects of antidepressants on the hypothalamic-pituitary-adrenal axis. 1729 2


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