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)

Intestinal P-glycoprotein, which is encoded by the MDR1 gene, plays an important role in the absorption and presystemic elimination of many xenobiotics. Hence, an understanding of the factors regulating its expression and function is of substantial interest. In addition to genetic factors, exposure to drugs such as rifampin can profoundly affect its expression. So far, the mechanisms by which rifampin induces MDR1 expression are poorly understood. Recent studies demonstrate that the nuclear receptor PXR (pregnane X receptor) is involved in xenobiotic induction of CYP3A4. Because CYP3A4 and MDR1 are often co-induced, we investigated whether a similar mechanism is also involved in MDR1 induction. The human colon carcinoma cell line LS174T was used as an intestinal model to study induction because in these cells the endogenous MDR1 gene is highly inducible by rifampin. The 5'-upstream region of human MDR1 was examined for the presence of potential PXR response elements. Several binding sites were identified that form a complex regulatory cluster at about -8 kilobase pairs. Only one DR4 motif within this cluster is necessary for induction by rifampin. We conclude that induction of MDR1 is mediated by a DR4 motif in the upstream enhancer at about -8 kilobase pairs, to which PXR binds.
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PMID:Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. 1129 22

Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The potency and hierarchy of bile acids as ligands for the farnesyl/bile acid receptor (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyte cultures. FXR:RXR heterodimers bound to IR1 elements and enhanced bile acid transcriptional activation of the mouse and human BSEP/SPGP promoters. In FXR/BAR nullizygous mice, which have dramatically reduced BSEP/SPGP levels, hepatic CYP3A11 and CYP2B10 were strongly but unexpectedly induced. Notably, the rank order of bile acids as CYP3A4 inducers and activators of pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR) closely paralleled each other but was markedly different from their hierarchy and potency as inducers of BSEP in human hepatocytes. Moreover, the hepatoprotective bile acid ursodeoxycholic acid, which reverses hydrophobic bile acid hepatotoxicity, activates PXR and efficaciously induces CYP3A4 (a bile-metabolizing enzyme) in primary human hepatocytes thus providing one mechanism for its hepatoprotection. Because serum and urinary bile acids increased in FXR/BAR -/- mice, we evaluated hepatic transporters for compensatory changes that might circumvent the profound decrease in BSEP/SPGP. We found weak MRP3 up-regulation. In contrast, MRP4 was substantially increased in the FXR/BAR nullizygous mice and was further elevated by cholic acid. Thus, enhanced hepatocellular concentrations of bile acids, due to the down-regulation of BSEP/SPGP-mediated efflux in FXR nullizygous mice, result in an alternate but apparent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporters that is consistent with activation of PXR/SXR by bile acids.
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PMID:Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. 1150 73

A wide variety of transporters and enzymes are involved in the disposition and metabolism of therapeutic drugs. Any compounds interacting with these proteins may inhibit uptake, efflux and/or metabolism of drugs and therefore alter the bioavailability and/or clearance of them. Progress in pharmacogenomics throws light on the clarification of mechanisms on drug-drug interaction. Various mutation and polymorphisms in drug transporters and metabolic enzymes were identified and some of which alter function of the proteins. The steroid and xenobiotic receptor, SXR, coordinately regulated CYP3A4, a major drug metabolizing enzyme and P-glycoprotein, a broad-specificity efflux pump. Now we are in the face of new period of study on drug interaction. With the help of pharmacogenomics, it might be possible to someday predict, avoid or manipulate potential cause of drug-drug interactions.
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PMID:[Analysis of the mechanisms of the drug-drug interaction from a view of pharmacogenomics]. 1180 42

P-glycoprotein (P-gp), the product of the multiple drug resistance (mdr) gene, can actively pump toxic drugs out of cells, but its pathophysiologic role is not yet fully understood. In this study, we examined the expression of P-gp in dextran sodium sulfate (DSS)-induced colitis in mice. Eight-week-old Balb/c female mice were given drinking water containing 7% DSS ad libitum for 7 days. Mice receiving DSS were sacrificed on days 3, 5, and 7 for histopathologic study. Tissue samples were examined by hematoxylin and eosin (HE) staining, and immunostained against mdr, CD4+, CD8+, and B220+. RNA was isolated from the large intestine and the expression of mdr1a was determined by RT-PCR. The function of P-gp was evaluated by rhodamine123 efflux using the everted sac method. The induction of colitis in mice was confirmed by body weight changes, HE staining and immunohistological grading of the large intestine with reference to CD4+, CD8+, and B220+ after 7 days of treatment. Severe inflammation was observed in the large, but not the small, intestine on day 7. The expression of mdr1a in the large intestine was reduced on days 3, 5, and 7. In addition, the P-gp function and the expression of PXR were also reduced in the large intestine of DSS-treated mice on day 3. This reduction was consistent with the immunohistologic observations. The expression of the mdr1a gene was reduced before severe symptoms appeared. These results suggest that P-gp expression may be related to the pathology of colitis.
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PMID:Altered expression and function of P-glycoprotein in dextran sodium sulfate-induced colitis in mice. 1258 18

During the past several years, important advances have been made in our understanding of the mechanisms that regulate the expression of genes that determine drug clearance, including phase I and phase II drug-metabolising enzymes and drug transporters. Orphan nuclear receptors have been recognised as key mediators of drug-induced changes in both metabolism and efflux mechanisms. In this review, we summarise recent findings regarding the function of nuclear receptors in regulating drug-metabolising and transport systems, and the relevance of these receptors to clinical drug-drug interactions and the development of new drugs. Emphasis is given to two newly recognised 'orphan' receptors (the pregnane X receptor [PXR] and the constitutive androstane receptor [CAR]) and their regulation of cytochrome P450 enzymes, such as CYP3A4, CYP2Cs and CYP2B6; and transporters, such as P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs) and organic anion transporter peptide 2 (OATP2). Although 'cross-talk' occurs between these two receptors and their target sequences, significant species differences exist between ligand-binding and activation profiles for both receptors, and PXR appears to be the predominant or 'master' regulator of hepatic drug disposition in humans. Several important physiological processes, such as cholesterol synthesis and bile acid metabolism, are also tightly controlled by certain ligand-activated orphan nuclear receptors (farnesoid X receptor [FXR] and liver X receptor [LXR]). In general, their ability to bind a broad range of ligands and regulate an extensive array of genes that are involved in drug clearance and disposition makes these orphan receptors attractive targets for drug development. Drugs have the capacity to alter nuclear receptor expression (modulators) and/or serve as ligands for the receptors (agonists or antagonists), and thus can have synergistic or antagonistic effects on the expression of drug-metabolising enzymes and transporters. Coadministration of drugs that are nuclear receptor agonists or antagonists can lead to severe toxicity, a loss of therapeutic efficacy or an imbalance in physiological substrates, providing a novel molecular mechanism for drug-drug interactions.
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PMID:Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. 1467 87

Although traditionally the liver was considered the main site of pharmacokinetic drug interactions, this view has been reexamined in light of the finding that cytochrome P4503A4 (CYP3A) enzymes are expressed at high levels in mature villus tip enterocytes. Because of their topographic location in small intestinal enterocytes and their overlap in substrates, functional interactions between P-glycoprotein and CYP3A were suggested. Although the functional interaction between CYP3A and P-glycoprotein is not yet completely understood, experimental evidence suggests several mechanisms: (1) CYP3A and P-glycoprotein are coregulated via the orphan nuclear receptor SXR/PXR; (2) drugs are repeatedly taken up and pumped out of the enterocytes by P-glycoprotein, and repeated exposure to CYP3A enzymes increases the probability of a drug being metabolized; (3) P-glycoprotein keeps intracellular drug concentrations within the linear range of CYP3A enzymes; (4) metabolism results in better substrates for P-glycoprotein; and (5) metabolism shifts affinity to other intestinal efflux transporters to avoid competitive interaction of metabolites with P-glycoprotein-mediated efflux of the parent drug.
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PMID:Transport proteins and intestinal metabolism: P-glycoprotein and cytochrome P4503A. 1522 47

P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) constitute a physiologic barrier in the intestine for many of the same substrates. Their expression can be influenced by nuclear receptor NR1I2 (pregnane X receptor; PXR), which acts as a receptor for various endobiotics and xenobiotics. However, P-gp and CYP3A4 are not identical in anatomic localization, suggesting unique as well as shared regulatory mechanisms of gene expression. We used established human colon carcinoma cell lines (LS180 and Caco-2) and measured mRNA and protein levels in cells after exposures to levothyroxine (L-T(4)), triiodo-L-thyronine (L-T(3)), and rifampin. Results indicate that L-T(4), L-T(3), and rifampin can upregulate the expression of P-gp mRNA and protein in LS180 cells, but only L-T(4) and L-T(3) can produce the same effect in Caco-2 cells, which are relatively lacking in PXR. In addition, L-T(4) and L-T(3) did not affect the expression of CYP3A4 in either cell line. We conclude that P-gp, but not CYP3A4, can be up-regulated by thyroid hormones in vitro by a PXR-independent mechanism. Considering the widespread prescription use of L-T(4) preparations in the older adult population, these results may be important for the clinical consideration of drug-drug interactions mediated by P-gp.
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PMID:Levothyroxine up-regulates P-glycoprotein independent of the pregnane X receptor. 1525

P-glycoprotein (PGP) substrates with high membrane permeability, such as propranolol and verapamil, are considered to be essentially "transparent" to PGP since the transporter does not significantly limit their absorption or elimination. However, the question of whether such compounds can modulate PGP expression in epithelial cells following short-term exposure, with potential consequences for drug interactions, has not been addressed. LS180 colonic epithelial cells were exposed to propranolol or verapamil at concentrations (50-300 microM) consistent with those likely to be present in the gut lumen during oral dosing. Both compounds stimulated four to six-fold increases in MDR1 mRNA and PGP protein expression measured by quantitative real-time PCR and immunoblotting, respectively. These changes were accompanied by an induction in transporter activity measured by rhodamine 123 efflux. In contrast, metoprolol, a compound with similar permeability but no affinity for PGP had no effect on PGP expression. The induction of PGP by propranolol and verapamil was rapid with significant increases occurring within 3h with maximal stimulation after 6h exposure. Rifampicin, shown to cause clinical drug interactions via a PXR-mediated increase in PGP expression, exhibited a very similar time-course and extent of induction. In conclusion, verapamil and propranolol, whose trans-epithelial permeability are unaffected by PGP, appear to be effective inducers of PGP expression in gut epithelial cells in vitro. While the in vivo significance of these observations is unknown, this questions whether high permeability, "PGP-transparent" compounds, currently favoured in drug selection strategies, should be evaluated in terms of their potential for transporter-mediated drug interactions.
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PMID:Rapid induction of P-glycoprotein expression by high permeability compounds in colonic cells in vitro: a possible source of transporter mediated drug interactions? 1527 86

P-glycoprotein, an ATP-driven drug export pump, is a critical, selective component of the blood-brain barrier responsible for the poor penetration of many therapeutic drugs. In liver, ligand-activated, nuclear receptors are transcriptional regulators of drug metabolizing enzymes and drug export pumps, but only one, the pregnane X receptor (PXR in rodents, SXR in humans), regulates p-glycoprotein expression. We report for the first time that PXR is expressed in rat brain capillaries. Moreover, exposing isolated capillaries to the PXR ligands pregnenolone-16alpha-carbonitrile (PCN) and dexamethasone increased p-glycoprotein expression and p-glycoprotein-specific transport of a fluorescent cyclosporine A derivative into capillary lumens. Dosing rats with PCN and dexamethasone increased p-glycoprotein expression in liver plasma membranes and in brain capillaries and up-regulated specific transport in capillaries. This is the first evidence for PXR expression in brain and for regulation by nuclear receptors of a xenobiotic export pump at the blood-brain barrier. These results imply selective tightening of the barrier in patients exposed to the wide range of xenobiotics that are PXR/SXR ligands, including drugs, dietary constituents, and toxicants.
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PMID:Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier. 1532 32

The purpose of this paper is to review preclinical and clinical evidence relating to drug interactions with preparations of the medicinal herb St John's wort (Hypericum perforatum). A systematic literature search was carried out in three electronic databases up to June 2004. Information about case reports classified as St John's wort drug interactions was retrieved from the WHO Collaborating Centre for International Drug Monitoring and from the UK Medicines and Healthcare products Regulatory Agency in June 2003. Against the background of proven efficacy in mild to moderate depressive disorders and an excellent tolerability profile in monotherapy, there is sufficient evidence from interaction studies and case reports to suggest that St John's wort may induce the cytochrome P450 (CYP) 3A4 enzyme system and the P-glycoprotein drug transporter in a clinically relevant manner, thereby reducing efficacy of co-medications. Drugs most prominently affected and contraindicated for concomitant use with St John's wort are metabolised via both CYP3A4 and P-glycoprotein pathways, including HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors (only CYP3A4), the immunosuppressants ciclosporin and tacrolimus, and the antineoplastic agents irinotecan and imatinib mesylate. Efficacy of hormonal contraceptives may be impaired as reflected by case reports of irregular bleedings and unwanted pregnancies. Drugs with a narrow therapeutic index should be monitored more closely when St John's wort is added, discontinued or the dosage is changed. The St John's wort constituent hyperforin is probably responsible for CYP3A4 induction via activation of a nuclear steroid/pregnane and xenobiotic receptor (SXR/PXR) and hypericin may be assumed to be the P-glycoprotein inducing compound, although the available evidence is less convincing. Combinations of St John's wort with serotonergic agents and other antidepressants should be restricted to prescription-only, by experienced clinicians, due to potential central pharmacodynamic interactions. In conclusion, providing certain precautions and contraindications are followed, and adequate information is given to healthcare professionals and patients, the safe and effective use of quality-tested St John's wort products can be ensured.
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PMID:Drug interactions with St John's wort : mechanisms and clinical implications. 1535 Jan 51


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