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

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

Epidemiological data suggest that environmental factors may trigger autoimmunity in genetically susceptible individuals. In primary biliary cirrhosis (PBC), it has been postulated that halogenated xenobiotics can modify self-molecules, facilitating the breakdown of tolerance to mitochondrial antigens. The transport and metabolism of xenobiotics is highly dependent on key genetic polymorphisms that alter enzymatic phenotype. We analyzed genomic DNA from 169 patients with PBC and 225 geographically and sex-matched healthy subjects for polymorphisms of genes coding for cytochromes P450 (CYPs) 2D6 (CYP2D6*4, CYP2D6*3, CYP2D6*5, and CYP2D6*6) and 2E1 (cl/c2), multidrug resistance 1 (MDR1 C3435T) P-glycoprotein, and pregnane X receptor (PXR C-25385T, C8055T, and A7635G). We compared the genotype frequencies in patients and controls and also correlated polymorphisms with PBC severity. The distributions of the studied genotypes did not significantly differ between patients and controls. However, when clinical characteristics of patients with PBC were compared according to genotype, the CYP2E1 c2 allele was associated with signs of more severe disease. In conclusion, genetic polymorphisms of CYP 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of PBC.
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PMID:Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis. 1569 Apr 82

Clinical findings indicate that co-administration of the isoxazolyl-penicillin flucloxacillin with cyclosporine may reduce the plasma concentrations of cyclosporine. We have explored in the present study if induction of cytochrome P450 3A4 or P-glycoprotein may offer a mechanistic explanation of the observed effects. Flucloxacillin is neither an inhibitor nor a substrate of drug metabolizing cytochrome P450 isoenzymes (CYP3A4, 1A2, 2C9, 2C19 and 2D6) or P-glycoprotein as shown by an in vitro assay for CYP inhibition, a fluorescent indicator assay for P-glycoprotein inhibition and a functional P-glycoprotein ATPase assay. However, incubation of human LS 180 colorectal adenocarcinoma cells with flucloxacillin led to a dose-dependent induction of MDR1 as well as of CYP3A4 mRNA, which was also confirmed in primary human hepatocytes. At high concentrations, flucloxacillin activated the human Pregnane-X-Receptor, PXR, a ligand-dependent transcription factor that is the target of many drugs that induce CYP3A4, with consequences for the metabolism of other drugs. Liver microsomes from control rats or rats, which received for 3 consecutive days 100 mg/kg of oral flucloxacillin, were used to study the metabolism and metabolite pattern of midazolam, a model substrate of CYP 3A4. There was a trend towards a higher intrinsic microsomal clearance of midazolam using microsomes from flucloxacillin treated rats. In addition, there was a significant increase in the formation of the principal midazolam metabolites 1-hydroxy midazolam, 4-hydroxy midazolam and 1,4-dihydroxy midazolam as compared to controls. These findings indicate that flucloxacillin has the potential to induce expression of both CYP3A4 as well as P-glycoprotein, most likely through activation of the nuclear hormone receptor PXR. This would offer an explanation for the observed clinical drug-drug interactions between the antibiotic and cyclosporine.
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PMID:Induction of cytochrome P450 3A4 and P-glycoprotein by the isoxazolyl-penicillin antibiotic flucloxacillin. 1647 2

Intestinal induction of Pgp is known to limit the oral availability of certain drug compounds and give rise to detrimental drug-drug interactions. We have investigated the induction of P-glycoprotein (Pgp; MDR1) activity in a human intestinal epithelial cell line (T84) following pre-exposure to a panel of drug compounds, reported to be Pgp substrates, inhibitors or inducers. Human MDR1-transfected MDCKII epithelial monolayers were used to assess Pgp substrate interactions and inhibition of digoxin secretion by the selected drug compounds. The T84 cell line was used to assess induction of Pgp-mediated digoxin secretion following pre-exposure to the same compounds. Changes in gene expression (MDR1, MRP2, PXR and CAR) were determined by quantitative RT-PCR. Net transepithelial digoxin secretion was increased (1.3 fold, n=6, P<0.05) following pre-exposure to the PXR activator hyperforin (100nM, 72h), as was MDR1 mRNA expression (3.0 fold, n=4, P<0.05). A number of Pgp substrates (quinidine, amprenavir, irinotecan, topotecan, atorvastatin and erythromycin) induced net digoxin secretion, as did the non-Pgp substrate artemisinin. Various non-Pgp substrates demonstrated inhibition of digoxin secretion (verapamil, mifepristone, clotrimazole, mevastatin, diltiazem and isradipine) but did not induce Pgp-mediated digoxin secretion. Of the compounds that increased Pgp secretion, quinidine, topotecan, atorvastatin and amprenavir pre-exposure also elevated MDR1 mRNA levels, whereas erythromycin, irinotecan and artemisinin displayed no change in transcript levels. This indicates possible post-translational regulation of digoxin secretion. Finally, a strong correlation between drug modulation of MRP2 and PXR mRNA expression levels was evident.
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PMID:Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84). 1870 21

Pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a role not only in drug metabolism and transport but also in various other biological processes. Ginkgo biloba is a herbal medicine commonly used to manage memory impairment. Treatment of primary cultures of rat hepatocytes with G. biloba extract increases the mRNA expression of CYP3A23, which is a target gene for rat PXR. The present study was conducted to test the hypothesis that G. biloba extract activates PXR. Treatment of mouse PXR (mPXR) or human PXR (hPXR)-transfected HepG2 cells with G. biloba extract at 200 microg/ml increased mPXR and hPXR activation by 3.2- and 9.5-fold, respectively. Dose-response analysis showed a log-linear increase in hPXR activation by the extract over the range of 200 to 800 microg/ml. To determine whether G. biloba extract induces hPXR target gene expression, cultured LS180 human colon adenocarcinoma cells were treated for 72 h with the extract. G. biloba extract at 200, 400, and 800 microg/ml increased CYP3A4 mRNA expression by 1.7-, 2.4-, and 2.5-fold, respectively. The same concentrations of the extract increased CYP3A5 (1.3-3.6-fold) and P-glycoprotein (ABCB) 1 (2.7-6.4-fold) mRNA expression. At concentrations (5 and 10 microM) that did not down-regulate PXR gene expression and were not cytotoxic, L-sulforaphane (an hPXR antagonist) decreased CYP3A4, CYP3A5, and ABCB1 gene expression in cells treated with G. biloba extract. In summary, G. biloba extract activated mPXR and hPXR in a cell-based reporter gene assay and induced CYP3A4, CYP3A5, and ABCB1 gene expression in hPXR-expressing LS180 cells.
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PMID:Identification of Ginkgo biloba as a novel activator of pregnane X receptor. 1872 5

A major concern regarding the chronic administration of antiretroviral drugs is the potential for induction of drug efflux transporter expression (i.e., P-glycoprotein, P-gp) at tissue sites that can significantly affect drug distribution and treatment efficacy. Previous data have shown that the inductive effect of human immunodeficiency virus protease inhibitors (PIs) is mediated through the human orphan nuclear receptor, steroid xenobiotic receptor (SXR or hPXR). The objectives of this study were to investigate transport and inductive properties on efflux drug transporters of two PIs, atazanavir and ritonavir, at the blood-brain barrier by using a human brain microvessel endothelial cell line, hCMEC/D3. Transport properties of PIs by the drug efflux transporters P-gp and multidrug resistance protein 1 (MRP1) were assessed by measuring the cellular uptake of (3)H-atazanavir or (3)H-ritonavir in P-gp and MRP1 overexpressing cells as well as hCMEC/D3. Whereas the P-gp inhibitor, PSC833, increased atazanavir and ritonavir accumulation in hCMEC/D3 cells by 2-fold, the MRP inhibitor MK571 had no effect. P-gp, MRP1, and hPXR expression and localization were examined by Western blot analysis and immunogold cytochemistry at the electron microscope level. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well-established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P-gp expression by 1.8-, 6-, and 2-fold, respectively, with no effect observed for MRP1 expression. In hCMEC/D3 cells, cellular accumulation of these PIs appears to be primarily limited by P-gp efflux activity. Long-term exposure of atazanavir or ritonavir to brain microvessel endothelium may result in further limitations in brain drug permeability as a result of the up-regulation of P-gp expression and function.
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PMID:Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. 1885 43

In the present study, the ability of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), also known as statins, to regulate the gene expression and function of multidrug resistance protein 1 (MDR1/P-glycoprotein) and differences between their acid and lactone forms were examined in human intestinal epithelial LS180 cells. Some statins had the potential to induce the expression of mRNAs for MDR1 and/or CYP3A in either form. The change in the mRNA expression of MDR1 was accompanied by a change in the CsA-dependent intracellular accumulation of rhodamine 123. Simvastatin lactone, but not the acid form, exhibited a strong inductive effect on the mRNA expression of MDR1 and CYP3A in a dose-dependent manner. Sulforaphane significantly suppressed the expression of MDR1 and CYP3A mRNAs induced by atorvastatin lactone, lovastatin acid, and lovastatin lactone, comparable to the control level, and moderately inhibited that by cerivastatin acid, fluvastatin acid and simvastatin lactone. In the case of pitavastatin acid, sulforaphane had no significant effect on the expression of MDR1 mRNA.These results suggested that some statins could induce MDR1 and CYP3A gene expression and these inductive effects differed between the lactone and active hydroxy acid forms, and that PXR-mediated regulation was rarely associated with the mRNA inducibility by pitavastatin acid, unlike that by other statins.
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PMID:Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. 1942 19

ABCB1 (P-glycoprotein) is an efflux transporter that limits the cellular uptake levels of various drugs in intestine, brain, and other tissues. The expression of human ABCB1 has recently been reported to be under the control of nuclear receptor NR1I subfamily members, pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3). Here, we have investigated the involvement of another NR1I member, vitamin D receptor (VDR, NR1I1), in ABCB1 expression. In the human colorectal adenocarcinoma cell line LS174T, which abundantly expresses VDR, both 1alpha,25-dihydroxyvitamin D(3) (1,25-VD3) and lithocholic acid (LCA) increased ABCB1 mRNA levels. Reporter gene assays in LS174T cells with constructs containing various lengths of the ABCB1 regulatory region revealed that the region containing multiple nuclear receptor binding motifs located at -7.8 kilobases [termed nuclear receptor-responsive module (NURREM)], to which PXR and CAR also bind, is essential for the VDR-mediated ABCB1 transactivation. Further reporter assays with constructs containing truncated NURREM and gel shift assays suggested simultaneous binding of multiple VDR/retinoid X receptor alpha heterodimers to NURREM. Furthermore, knockdown of VDR expression in LS174T cells blocked the LCA- and the 1,25-VD3-induced transcription of ABCB1 reporter genes. In human hepatoma HepG2 cells, in contrast with LS174T cells, 1,25-VD3 activated the ABCB1 transcription only in the presence of ectopically expressed VDR. These results suggest that the NR1I subfamily members regulate the ABCB1 expression sharing the binding sites within NURREM and that the physiologically produced LCA and 1,25-VD3 may modulate the ABCB1 expression in human intestines, possibly associated with interindividual variations of ABCB1 expression.
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PMID:Involvement of Vitamin D receptor in the intestinal induction of human ABCB1. 1946 Sep 46

The orphan nuclear receptor pregnane X receptor regulates enzymes and transport proteins involved in the detoxification and clearance of numerous endobiotic and xenobiotic compounds, including pharmaceutical agents. Multiple alternatively spliced pregnane X receptor isoforms have been identified which are significantly expressed in humans and mice (up to 30% of the total pregnane X receptor transcript), however, little is known about their biological action. We explored functional differences between the major mouse pregnane X receptor isoforms mPXR(431) and mPXR(Delta171-211) that lacks 41 amino acids adjacent to the ligand-binding pocket. Transient transfection assays showed that mPXR(Delta171-211) reduced the basal transcription of cytochrome P450 3A4 and the drug transporter P-glycoprotein/Multi Drug Resistance Protein 1 and directly repressed the regulatory effects of mPXR(431) on these genes. Replacement of the mPXR(Delta171-211) DNA-binding domain with that of GAL4 showed mPXR(Delta171-211) retained its repressive role independent of binding to PXR responsive elements located within the cytochrome P450 3A4 and Multi Drug Resistance Protein 1 regulatory regions. Use of the histone deacetylase inhibitor, trichostatin A, demonstrated that the repressive function of mPXR(Delta171-211) acts independently of histone acetylation state. Protein interaction assays revealed mPXR(Delta171-211) and mPXR(431) differentially bind the obligatory heterodimer partner retinoid X receptor. Furthermore, mPXR(431) and mPXR(Delta171-211) proteins could heterodimerize. These studies demonstrate that the variant mouse PXR isoform, mPXR(Delta171-211), has a distinct repressive function from mPXR(431) in regulating genes encoding important drug metabolizing enzymes and transport proteins.
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PMID:The alternatively spliced murine pregnane X receptor isoform, mPXR(delta171-211) exhibits a repressive action. 2006 Sep 28

The efficacy of drugs acting within lymphocytes depends on their intracellular concentrations, which could be modulated by membrane efflux transporters including P-glycoprotein (P-gp), encoded by the MDR1 gene. In particular, P-gp induction may compromise the efficacy of its substrates. Rifampicin and phenobarbital have been shown to induce P-gp in hepatic and intestinal cells through the activation of the nuclear receptors PXR and CAR. However, controversial data exist in human lymphocytes. We investigated the effect of these drugs on P-gp activity and expression in lymphocytes in vitro and ex vivo. CCRF-CEM cells and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were incubated in the presence of rifampicin, phenobarbital, or without any drug. P-gp activity was measured by flow cytometry using DiOC(6) efflux. MDR1, PXR and CAR mRNA expression were measured by quantitative RT-PCR. Neither P-gp activity nor MDR1 mRNA expression were modified by rifampicin or phenobarbital both in CCRF-CEM cells and PBMCs. Moreover, P-gp protein expression at the membrane was neither detectable nor induced. The very weak PXR and CAR mRNA expression levels in these cells could partly explain these results. Therefore, P-gp induction by rifampicin and phenobarbital may play a negligible role in drug interactions occurring within lymphocytes.
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PMID:Lack of P-glycoprotein induction by rifampicin and phenobarbital in human lymphocytes. 2048 28

A number of studies have identified differential kavalactone activity against a variety of molecular targets, including P-glycoprotein (Pgp), platelet monoamine oxidase (MAO-B), transcription factor binding domains, pregnane X (PXR) and GABA receptors, and cytochrome P450 and cyclo-oxygenase (COX) enzymes. The molecular structure of the kavalactones possesses a pharmacophore for several of these targets. In most cases, conformational stability is more significant than the substituents present. The analysis of these pharmacophores provides important insights for future medicinal chemistry-based approaches to kavalactone-type drugs.
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PMID:Kavalactone pharmacophores for major cellular drug targets. 2103 4


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