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)

Why some patients with seizures are successfully treated with antiepileptic drugs (AEDs) and others prove medically intractable is not known. Inadequate intraparenchymal drug concentration is a possible mechanism of resistance to AEDs. The multiple drug resistance gene (MDR1) encodes P-glycoprotein, an energy-dependent efflux pump that exports planar hydrophobic molecules from the cell. If P-glycoprotein is expressed in brain of some patients with intractable epilepsy and AEDs are exported by P-glycoprotein, lower intraparenchymal drug concentrations could contribute to lack of drug response in such patients. Eleven of 19 brain specimens removed from patients during operation for intractable epilepsy had MDR1 mRNA levels > 10 times greater than those in normal brain, as determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. Immunohistochemistry for P-glycoprotein from 14 of the patients showed increased staining in capillary endothelium in samples from epileptic patients as compared with staining in normal brain samples. In epileptic brain specimens with high MDR1 mRNA levels, expression of P-glycoprotein in astrocytes also was identified. Last, steady-state intracellular phenytoin (PHT) concentrations in MDR1 expressing neuroectodermal cells was one fourth that in MDR1-negative cells. MDR1 expression is increased in brain of some patients with medically intractable epilepsy, suggesting that the patients' lack of response to medication may be caused by inadequate accumulation of AED in brain.
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PMID:MDR1 gene expression in brain of patients with medically intractable epilepsy. 800

Major neurologic complications secondary to cyclosporine are well documented and are known to include confusion, cortical blindness, seizure, spasticity, paresis, ataxia and coma. Most previous reports attribute these to white matter central nervous system (CNS) lesions or white/grey matter border lesions. Many predisposing factors have been identified, including: elevated levels of cyclosporine, hypomagnesemia, hypocholesterolemia, aluminium toxicity, high dose steroids, hypertension and infection. However CNS events attributed to cyclosporine have been reported without any of these risk factors. We report a case of a child developing multiple white and grey matter thalamic and cortical lesions along with acute neurologic deterioration, and then review cyclosporine mediated CNS injury, including the roles of P-glycoprotein and cyclophilin.
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PMID:Cyclosporine-induced white and grey matter central nervous system lesions in a pediatric renal transplant patient. 1008 60

Intractable seizures are the most common manifestation in severe cases of tuberous sclerosis. Multidrug resistance type 1 (MDR1) gene expression is directly linked to the resistance of tumor cells to chemotherapy as the major cause of treatment failure, but it has not been reported in tuberous sclerosis cells nor has the relationship between the MDR1 gene and antiepileptic drugs been described. A 4-month-old female is described with poorly controlled seizures secondary to tuberous sclerosis. The patient was treated with antiepileptic drugs, including phenytoin, phenobarbital, and lorazepam, without improvement of symptoms. Phenytoin blood levels were invariably subtherapeutic and ranged from 0.45 to 3.55 microg/mL, despite several consecutive intravenous loading doses. Surgical treatment with total resection of the brain lesions was performed as a last resort. Immunohistochemical analysis of the resected tissues revealed high levels of P-glycoprotein 170 expression, the product of the MDR1 gene. Both MDR1 gene expression and persistently low phenytoin levels likely share a common pathway liable to induce drug-resistant epilepsy.
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PMID:Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy. 1058 Aug 86

Drug resistance in epilepsy due to malformations of cortical development (MCD) is unexplained. P-glycoprotein is a mediator of drug resistance, and we propose that MCD lesions over-express P-glycoprotein. Because P-glycoprotein expression may be induced by some antiepileptic drugs (AEDs), we studied brain samples from MCD cases before the onset of seizures or treatment with AEDs. Sixteen MCD cases and 16 age-matched controls were examined using immunohistochemistry. Glial labelling, representing over-expression, was seen in 10 of 16 MCD samples and in two of 16 control samples (p = 0.003). Semiquantitative assessment showed many immunoreactive glia in five of 16 MCD and one of 16 controls. We conclude that there is constitutive over-expression of P-glycoprotein in many MCD.
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PMID:Over-expression of P-glycoprotein in malformations of cortical development. 1059 58

P-glycoprotein is an ATP-dependent drug transport protein that is predominantly found in the apical membranes of various epithelial cell types in the body, including the blood luminar membrane of the brain capillary endothelial cells that make up the blood-brain barrier. Increased P-glycoprotein expression in the blood-brain barrier has been described in epileptogenic brain tissue of patients with pharmacoresistant epilepsy, suggesting that overexpression of P-glycoprotein may be involved in multidrug resistance of epilepsy. The mechanisms underlying the overexpression of P-glycoprotein in brain tissue of epileptic patients are not clear. Two antiepileptic drugs, phenobarbital and phenytoin, have been reported to up-regulate P-glycoprotein in cell cultures, so that chronic treatment with antiepileptic drugs may enhance P-glycoprotein expression in the blood-brain barrier. To directly address this possibility, we treated rats with phenobarbital or phenytoin over 11 days and subsequently determined expression of P-glycoprotein by immunohistochemistry in endothelium and parenchyma of several brain regions, including regions of the temporal lobe, which is often involved in pharmacoresistant types of epilepsy. Except for a moderate increase in the intensity of P-glycoprotein expression in the piriform/parietal cortex and cerebellum of phenobarbital-treated rats, no significant P-glycoprotein increases were seen after prolonged treatment with phenobarbital or phenytoin in any brain region examined. In view of recent findings that seizures lead to a transient induction of P-glycoprotein in the brain of rats, it seems reasonable to suggest that the overexpression of P-glycoprotein in brain regions of patients with intractable epilepsy is a consequence of uncontrolled seizures rather than of chronic treatment with antiepileptic drugs.
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PMID:Lack of effects of prolonged treatment with phenobarbital or phenytoin on the expression of P-glycoprotein in various rat brain regions. 1223 84

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

Long term treatment with antiepileptic drugs (AEDs) is the standard therapeutic approach to eradicate seizures. However, a small but significant number of patients fail AED treatment. Intrinsic drug resistance may depend on two main and not necessarily mutually exclusive mechanisms: 1) Loss of pharmacological target (e.g., GABAA receptors); 2) poor penetration of the drug into the central nervous system (CNS). The latter is due to the action of multiple drug resistance proteins capable of active CNS extrusion of drugs. These include MDR1 (P-glycoprotein, PgP), the multidrug resistance related proteins MRP1-5, and lung-resistance protein (LRP). Overexpression of MDR1 occurs in human epileptic brain. It has therefore been proposed that MDR1/PgP may contribute to multiple drug resistance in epilepsy. In addition to MDR1/PgP, other genes such as MRP2, MRP5, and human cisplatin resistance-associated protein are also overexpressed in drug-resistant epilepsy. In normal brain tissue MDR1/PgP is expressed almost exclusively by endothelial cells (EC), while in epileptic cortex both EC and perivascular astrocytes express MDR1/PgP. The underlying causes for tissue differences may be genomic (i.e., at the DNA level), or MDR1/PgP could be induced by seizures, previous drug treatment, or a combination of the above. We will present evidence showing that expression of multiple drug resistance genes in epilepsy is a complex phenomenon and that glial cells are involved. This second line of defense for xenobiotics may have profound implications for the pharmacokinetic properties of antiepileptic drugs and their capacity to reach neuronal targets.
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PMID:Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. 1269 50

In the brain, the efflux transporter P-glycoprotein (Pgp) is predominantly located on the luminal membrane of endothelial cells lining brain microvessels and forming the blood-brain barrier. Many lipophilic drugs, including antiepileptic drugs, are potential substrates for Pgp. Overexpression of Pgp in endothelial cells of the blood-brain barrier has been determined in patients with drug resistant forms of epilepsy such as temporal lobe epilepsy and rodent models of temporal lobe epilepsy and suggested to lead to reduced penetration of antiepileptic drugs into the brain. Expression of Pgp after seizures has also been described in astrocytes, whereas it is not clear whether neurons can express Pgp. In the present study, Pgp expression was studied by immunohistochemistry in rats 24 h after a status epilepticus induced by either pilocarpine or kainate, widely used models of temporal lobe epilepsy. Unexpectedly, in addition to endothelial Pgp staining, intense Pgp staining was found in neurons in the CA3c/CA4 sectors and hilus of the hippocampus formation, but not in other brain regions examined. The neuronal Pgp staining was confirmed by two different Pgp antibodies. Double immunolabeling and confocal microscopy showed that Pgp was colocalized with the neuronal marker neuronal nuclear antigen, but not with the glial marker glial fibrillary acidic protein. No neuronal Pgp staining was seen in control rats. The expression of Pgp in neurons after limbic seizures was substantiated by determining Pgp encoding genes (mdr1a, mdr1b) in neurons by real time quantitative RT-PCR. Increased Pgp expression in hippocampal neurons is likely to affect the action of drugs with intraneuronal targets and, in view of recent evidence from other cell types, could be associated with prevention of apoptosis which is involved in neuronal damage developing after seizures such as produced by pilocarpine.
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PMID:Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures. 1470 87

Drug transporters are increasingly recognized to be important to drug disposition and response. P-glycoprotein, the encoded product of the human MDR1 (ABCB1) gene, is of particular clinical relevance in that this transporter has broad substrate specificity, including a variety of structurally divergent drugs in clinical use today. Moreover, expression of this efflux transporter in certain tissue compartments such as the gastrointestinal tract and brain capillary endothelial cells limits oral absorption and central nervous system entry of many drugs. Recently, a number of single-nucleotide polymorphisms (SNPs) in MDR1 have been identified. An increasing number of studies have also implicated certain commonly occurring SNPs in MDR1 in problems including altered drug levels and host susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and CD4 cell recovery during human immunodeficiency virus therapy. However, in many such cases, the reported effects of MDR1 SNPs have been inconsistent and, in some cases, conflicting. In this review SNPs in MDR1 in relation to population frequencies, drug levels, and phenotypes are outlined. In addition, issues relating to MDR1 haplotypes, environmental factors, and study design, as potential confounding factors of the observed MDR1 polymorphism effect in vivo, are also discussed.
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PMID:Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. 1474 89

1. Failure of anticonvulsive drugs to prevent seizures is a common complication of epilepsy treatment known as drug-refractory epilepsy but their causes are not well understood. It is hypothesized that the multidrug resistance P-glycoprotein (Pgp-170), the product of the MDR-1 gene that is normally expressed in several excretory tissues including the blood brain barrier, may be participating in the refractory epilepsy. 2. Using two monoclonal antibodies against Pgp-170, we investigated the expression and cellular distribution of this protein in the rat brain during experimentally induced epilepsy. Repeated seizures were induced in male Wistar rats by daily administration of 3-mercaptopropionic acid (MP) 45 mg/kg i.p. for either 4 days (MP-4) or 7 days (MP-7). Control rats received an equivalent volume of vehicle. One day after the last injection, rats were sacrificed and brains were processed for immunohistochemistry for Pgp-170. As it was previously described, Pgp-170 immunostaining was observed in some brain capillary endothelial cells of animals from control group. 3. Increased Pgp-170 immunoreactivity was detected in MP-treated animals. Besides the Pgp-170 expressed in blood vessels, neuronal, and glial immunostaining was detected in hippocampus, striatum, and cerebral cortex of MP-treated rats. Pgp-170 immunolabeled neurons and glial cells were observed in a nonhomogeneous distribution. MP-4 animals presented a very prominent Pgp-170 immunostaining in the capillary endothelium, surrounding astrocytes and some neighboring neurons while MP-7 group showed increased neuronal labeling. 4. Our results demonstrate a selective increase in Pgp-170 immunoreactivity in the brain capillary endothelial cells, astrocytes, and neurons during repetitive MP-induced seizures. 5. The role for this Pgp-170 overexpression in endothelium and astrocytes as a clearance mechanism in the refractory epilepsy, and the consequences of neuronal Pgp-170 expression remain to be disclosed.
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PMID:Neuronal and glial expression of the multidrug resistance gene product in an experimental epilepsy model. 1504 12


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