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 (P-gp), a membrane protein that was originally found to be involved in the efflux of cytotoxic drugs out of the tumor cells, is also present in a variety of normal human and animal tissues, such as the adrenal cortex. The function of P-gp in the adrenal cortex has not been defined yet. The aim of our study was to determine whether the blockade of P-gp by cyclosporine A (CsA) dissolved in Cremophor EL (Crem) inhibits cortisol secretion in rabbits. In 14 rabbits, the baseline and ACTH stimulated serum cortisol levels were measured before and after CsA treatment. Seven rabbits were treated with 2 x 30 mg/kg CsA and seven with 2 x 90 mg/kg CsA injected s.c. Serum cortisol levels were determined by radioimmunoassay adjusted for expected values. The whole blood CsA levels were determined by a commercially available fluorescence polarization immunoassay. Serum cortisol levels, both baseline and ACTH stimulated, significantly increased after both low and high dose CsA treatment. The increase was dose dependent. The mean baseline cortisol levels increased from 5.7 (SD = 6.3) to 15.0 nmol/l (SD = 7.2) in the low dose group and from 7.7 (SD = 4.9) to 44.9 nmol/l (SD = 13.8) in the high dose group. The mean cortisol levels 8 h after ACTH stimulation increased from 53.3 (SD = 34.5) to 106.0 nmol/l (SD = 33.0) in the low dose group and from 47.7 (SD = 12.2) to 153.0 nmol/l (SD = 55.1) in the high dose group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclosporine A increases serum cortisol levels in rabbits. 757 69

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

The aim of this study is to evaluate whether the technetium-99m sestamibi ((99m)Tc-MIBI) single photon emission computed tomography (SPECT) characteristics of pituitary adenomas might be correlated with cavernous sinus invasion, proliferative potential or the multidrug-resistance (MDR-1) gene product P-glycoprotein (Pgp) expression in pituitary adenomas. Fifteen patients with pituitary adenomas, including 10 nonfunctioning adenomas, two prolactinomas, two GH producing adenomas, and one ACTH producing adenomas was investigated for this study. SPECT images with (99m)Tc-MIBI were acquired 15 minutes (early) and 3 hours (delayed) after injection. The tumor-to-normal brain ratio was calculated both early (ER) and delayed (DR) images. Retention index (RI) was calculated using the following formula: (DR-ER)/ERx100%. The pituitary adenomas specimens were examined by immunohistochemistry using anti-Pgp and MIB-1 monoclonal antibodies.(99m)Tc-MIBI SPECT findings were not related to MIB-1 labeling index or cavernous sinus invasion. (99m)Tc-MIBI SPECT RI (-38.55+/-20.77) of the Pgp-positive group was significantly lower than that (-15.78+/-19.40) of Pgp-negative group (p=0.0494). No significant difference was observed in the ER and DR of (99m)Tc-MIBI SPECT between Pgp-positive and negative groups. Our study suggests that although (99m)Tc-MIBI SPECT is not useful to evaluate the proliferative potential or cavernous sinus invasion of pituitary adenomas. (99m)Tc-MIBI SPECT could predict anti-cancer drug resistance related to the expression of Pgp in pituitary adenomas.
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PMID:Technetium-99m sestamibi single photon emission computed tomography findings correlated with P-glycoprotein expression in pituitary adenoma. 1695 66

Half of patients with nephrotic syndrome caused by primary focal segmental glomerulosclerosis (FSGS) have resistance to treatment with steroids. In the case of corticosteroid resistance,  the best evidence-based option has classically been treatment with calcineurin inhibitors,  although recent studies indicate that mycophenolate may have similar efficacy. In patients with resistance to calcineurin inhibitors,  there is no option that allows the clinical course of the disease to be modified, and this is supported by appropriately designed clinical trials, although observational studies have suggested the potential usefulness of mycophenolate, sirolimus, rituximab, apheresis or high galactose doses as treatment options. In FSGS of idiopathic origin, resistant to steroids and calcineurin inhibitors, before taking the decision whether or not to test other immunosuppressive drugs, it might be appropriate to conduct a systematic analysis that considers: 1) evaluating whether the dose and duration of treatment with steroids and calcineurin inhibitors were suitable, 2) analysing the level of P-glycoprotein expression in lymphocytes, 3) performing a new renal biopsy if there is no electron microscopic study available for the first, 4) in young patients,  considering a genetic study to rule out the presence of the podocin variant pR229Q in combination with heterozygous mutations in NPHS2,  and 5) evaluating the seriousness and difficulty of managing the nephrotic syndrome and the likelihood of progressive loss of renal function. Currently, there are multiple study avenues that attempt to identify the pathogenic mechanisms that cause podocyte injury and there are also several studies underway to analyse the efficacy of drugs such as adalimumab, fresolimumab, rosiglitazone, ACTH (corticotropin) or galactose at high doses, whose preliminary results have generated expectations that require confirmation in larger-scale clinical studies.  In the future, it is possible that a better understanding of the pathogenic pathway or pathways that cause FSGS may allow differentiation between immunomodulable and non-immunomodulable forms,  however, this continues to be a challenge currently.
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PMID:Treatment of idiopathic focal segmental glomerulosclerosis: options in the event of resistance to corticosteroids and calcineurin inhibitors. 2389 76