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)

P-glycoprotein (P-gp) is a major efflux transporter contributing to the efflux of a range of xenobiotic compounds at the blood-brain barrier (BBB). In the present study, we evaluated the P-gp function at the BBB using positron emission tomography (PET) in nonhuman primates. Serial brain PET scans were obtained in three rhesus monkeys after intravenous administration of [(11)C]verapamil under control and P-gp inhibition conditions ([PSC833 ([3'-keto-Me-Bmt(1)]-[Val(2)]-cyclosporin) 20 mg/kg/2 h]). The parent [(11)C]verapamil and its metabolites in plasma were determined by HPLC with a positron detector. The initial brain uptake clearance calculated from the integration plot was used for the quantitative analysis. After intravenous administration, [(11)C]verapamil was taken up rapidly into the brain (time to reach the peak, 0.58 min). The blood level of [(11)C]verapamil decreased rapidly, and it underwent metabolism with time. The inhibition of P-gp by PSC833 increased the brain uptake of [(11)C]verapamil 4.61-fold (0.141 versus 0.651 ml/g brain/min, p < 0.05). These results suggest that PET measurement with [(11)C]verapamil can be used for the evaluation of P-gp function at the BBB in the living brain.
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PMID:In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil. 1629 15

The Nrf2 (nuclear factor-erythroid 2 p45-related factor 2) transcription factor regulates gene expression of the GCLC (glutamate-cysteine ligase catalytic subunit), which is a key enzyme in glutathione synthesis, and GSTs (glutathione S-transferases) via the ARE (antioxidant-response element). The Mrp2 (multidrug-resistance protein 2) pump mediates the excretion of GSH and GSSG excretion as well as endo- and xeno-biotics that are conjugated with GSH, glucuronate or sulphate. Considering that Mrp2 acts synergistically with these enzymes, we hypothesized that the regulation of Mrp2 gene expression is also dependent on Nrf2. Using BHA (butylated hydroxyanisole), which is a classical activator of the ARE-Nrf2 pathway, we observed an increase in the transcriptional activity of Mrp2, GCLC and Gsta1/Gsta2 genes in the mouse liver. A similar pattern of co-induction of Mrp2 and GCLC genes was also observed in mouse (Hepa 1-6) and human (HepG2) hepatoma cells treated with BHA, beta-NF (beta-naphthoflavone), 2,4,5-T (trichlorophenoxyacetic acid) or 2AAF (2-acetylaminofluorene), suggesting that these genes share common mechanism(s) of transcriptional activation in response to exposure to xenobiotics. To define the mechanism of Mrp2 gene induction, the 5'-flanking region of the mouse Mrp2 gene (2.0 kb) was isolated, and two ARE-like sequences were found: ARE-2 (-1391 to -1381) and ARE-1 (-95 to -85). Deletion analyses demonstrated that the proximal region (-185 to +99) contains the elements for the basal expression and xenobiotic-mediated induction of the Mrp2 gene. Gel-shift and supershift assays indicated that Nrf2-protein complexes bind ARE sequences of the Mrp2 promoter, preferentially to the ARE-1 sequence. Overexpression of Nrf2 increased ARE-1-mediated CAT (chloramphenicol acetyltransferase) gene activity, while overexpression of mutant Nrf2 protein repressed the activity. Thus Nrf2 appears to regulate Mrp2 gene expression via an ARE element located at the proximal region of its promoter in response to exposure to xenobiotics.
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PMID:Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. 1642 33

The ATP-driven drug export pump, P-glycoprotein, is a primary gatekeeper of the blood-brain barrier and a major impediment to central nervous system (CNS) pharmacotherapy. Reducing P-glycoprotein activity dramatically increases penetration of many therapeutic drugs into the CNS. Previous studies in rat showed that brain capillary P-glycoprotein was transcriptionally up-regulated by the pregnane X receptor (PXR), a xenobiotic-activated nuclear receptor. Here we used a transgenic mouse expressing human PXR (hPXR) to determine the consequences of increased blood-brain barrier P-glycoprotein activity. P-glycoprotein expression and transport activity in brain capillaries from transgenic mice was significantly increased when capillaries were exposed to the hPXR ligands, rifampin and hyperforin, in vitro and when the mice were dosed with rifampin in vivo. Plasma rifampin levels in induced mice were comparable with literature values for patients. We also administered methadone, a CNS-acting, P-glycoprotein substrate, to control and rifampin-induced transgenic mice and measured the drug's antinociceptive effect. In rifampin-induced mice, the methadone effect was reduced by approximately 70%, even though plasma methadone levels were similar to those found in transgenic controls not exposed to rifampin. Thus, hPXR activation in vivo increased P-glycoprotein activity and tightened the blood-brain barrier to methadone, reducing the drug's CNS efficacy. This is the first demonstration of the ability of blood-brain barrier PXR to alter the efficacy of a CNS-acting drug.
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PMID:In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation. 1683 25

Resistance to anticancer drugs is often mediated by the overexpression of P-glycoprotein encoded by the multi-drug resistance (MDR1) gene. The nuclear receptor, steroid and xenobiotic receptor (SXR), is one of the key transcriptional regulators of MDR1 gene expression. A variety of xenobiotics bind to SXR, and stimulate transcription on xenobiotic-response elements (XREs), located in the MDR1 gene promoter. Diethylhexyl phthalate (DEHP) is widely used as a plasticizer for polyvinyl chloride (PVC) medical devices. Previous studies have shown that a significant amount of DEHP leaches from PVC infusion bags and lines during interventions, such as total parenteral nutrition, blood transfusion, and cancer chemotherapy. Thus, the leaching of DEHP during parenteral chemotherapy for cancer patients may facilitate MDR1 expression in various tissues, including cancer cells, which may promote drug resistance. To examine such a hypothesis, the effect of DEHP on SXR-mediated transcription of the MDR1 gene was studied in the human colon adenocarcinoma-derived cell line, LS174T cells, which endogenously express SXR. DEHP increased the SXR-mediated transcription of the MDR1 gene in luciferase-reporter assays. The induction by DEHP was abrogated when a reporter plasmid containing mutated DR+4 motif in the XRE was used. In a mammalian two-hybrid assay, DEHP recruited steroid receptor co-activator-1 to the ligand-binding domain of SXR. Finally, using real-time reverse transcriptase-PCR, we showed that DEHP increased MDR1 gene expression in a dose-dependent manner. We conclude that DEHP is an inducer of the MDR1 gene in this cell line. As such, the leaching of DEHP from the PVC medical devices may influence the MDR1 expression, which may induce resistance to drugs in certain populations of cancer cells.
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PMID:The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. 1700 90

In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the "chemoimmunity" network, which has a number of features reminiscent of classical immunology.
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PMID:Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system. 1701 88

Inherited differences in xenobiotic transport and metabolism may play an important role in the development of adult acute myeloid leukemia (AML) and response to the chemotherapy. An ATP-binding cassette (ABC) family transporter P-glycoprotein (P-gp or ABCB1), encoded by ABCB1 (MDR1) gene, is involved in the protection against xenobiotics and multi-drug resistance. The aim of this study was to investigate the potential involvement of the ABCB1 gene exon 26 3435C>T single nucleotide polymorphism (SNP) in the genetic susceptibility to AML and regulation of P-gp expression and activity in AML cells. A total of 180 adult AML patients and 180 sex-matched controls were genotyped using PCR-RFLP method. Moreover, in 40 AML patients ABCB1 gene expression was studied by real-time RT-PCR and P-gp expression and activity were assessed by flow cytometry assays. The prevalence of 3435C>T ABCB1 polymorphism was similar in patient and control cohorts (P = 0.16). Furthermore, the carriers of different ABCB1 genotypes did not differ significantly according to ABCB1 gene expression (P = 0.99), P-gp expression (P = 0.42) and P-gp activity (P = 0.83) in leukemic cells. The authors conclude that isolated 3435C>T ABCB1 SNP is not a major factor of the genetic susceptibility to adult AML, and that genotyping of this polymorphism does not allow predicting P-gp expression or activity in AML cells.
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PMID:No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells. 1703 91

Functional single nucleotide polymorphism (SNP) C3435T in exon 26 of the MDR1 ( ABCB1 ) gene encoding the xenobiotic transporter P-glycoprotein (P-gp, MDR1, ABCB1) may influence susceptibility to several diseases as well as clinical outcome of treatment with P-gp substrates. Exposure to environmental chemicals is thought to be involved in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) and P-gp-transported drugs are used in its treatment; however, little is known about the impact of the C3435T MDR1 SNP in B-CLL. In this study, 110 Caucasian B-CLL patients and 201 healthy controls were genotyped for the MDR1 C3435T SNP. Additionally, P-gp activity was assessed in malignant lymphocytes of 22 untreated B-CLL patients. We observed a higher frequency of carriers of at least one 3435T allele (3435CT and 3435TT genotypes) among B-CLL patients as compared to normal individuals (76% vs . 63%, p=0.027). The genotypes 3435CT and 3435TT were associated with B-CLL, (odds ratio=1.8, 95% confidence interval = 1.1-3.0). Moreover, P-gp activity in B-CLL cells depended on MDR1 genotype, with the highest P-gp activity in 3435CC homozygotes, intermediate in 3435CT heterozygotes and the lowest in 3435TT homozygotes (p=0.042). P-gp activity was also significantly lower in carriers of the T-allele (3435CT/TT genotype) as compared to the non-carriers (3435CC genotype), (p=0.029). Taken together, these data indicate that the MDR1 C3435T SNP may carry an increased risk of developing B-CLL, possibly by virtue of decreased protection against P-gp-substrate carcinogens. The differences in P-gp activity in B-CLL tumor cells related to MDR1 genotype may have implications to the response to chemotherapy with P-gp transported anticancer agents.
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PMID:MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia. 1708 64

In 1976, Juliano and Ling(1) reported expression of a 170 kDa protein in colchicine-resistant Chinese hamster ovary (CHO) cells that was absent in drug-sensitive cells. Because this protein altered cellular permeability to colchicine, the authors named it P-glycoprotein (P-gp).(1) P-gp overexpression was described in tumor samples and leukemic cells.(2) High homology with bacterial transporters suggested that P-gp was an efflux transporter, modulating intracellular xenobiotic concentrations.(3) In 1986, the gene encoding P-gp was discovered and designated MDR1 (HUGO name ABCB1).(4) Immunohistochemical studies demonstrated P-gp expression in tissues with secretory or excretory functions (liver, kidney, and gastrointestinal tract) and at blood-tissue barrier sites, such as the blood-brain barrier.(5) This pattern of expression indicated that P-gp may influence xenobiotic response and toxicity, either through pharmacokinetic or pharmacodynamic effects.(6)
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PMID:ABCB1 pharmacogenetics: progress, pitfalls, and promise. 1725 50

The PLHC-1 hepatoma cell line derived from topminnow (Poeciliopsis lucida) is one of the most frequently used fish cell lines in aquatic ecotoxicology. These cells have been well characterized regarding the presence of phase I and phase II enzymes involved in the metabolism of xenobiotics. However, the presence of the ABC transport proteins possibly involved in the MultiXenobiotic Resistance (MXR) mechanism as phase III of cellular detoxification has never been described in the PLHC-1 cells. The main goal of this study was the detection and functional characterization of toxicologically relevant xenobiotic efflux transporters from ABCB and ABCC subfamily in the PLHC-1 cells. Using specific primer pairs two PCR products 1769 and 1023bp in length were successfully cloned and sequenced. Subsequent multiple alignment and phylogenetic analysis showed that these sequences share a high degree of homology with the P-glycoprotein (Pgp1; ABCB1) and the MRP3 (ABCC3). Functional experiments with fluorescent model substrates and specific inhibitors were used to verify that transport activities of Pgp- and MRP-related proteins are indeed present in PLHC-1 cells. Accumulation or efflux/retention rates of rhodamine 123, calcein-AM or monochlorbimane were time- and concentration-dependent. Cyclosporine A, MK571, verapamil, reversine 205, indomethacine and probenecid were used as specific inhibitors of Pgp1 and/or MRPs transport activities, resulting in a dose dependent inhibition of related transport activities in PLHC-1 cells. Similar to mammalian systems, the obtained IC(50) values were in the lower micromolar range. Taken together these data demonstrate that: (1) the PLHC-1 cells do express a functional MXR mechanism mediated by toxicologically relevant ABC efflux transporters; and (2) the presence of all three critical phases of cellular detoxification additionally affirms the PLHC-1 cells as a reliable in vitro model in aquatic toxicology.
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PMID:Detection and functional characterization of Pgp1 (ABCB1) and MRP3 (ABCC3) efflux transporters in the PLHC-1 fish hepatoma cell line. 1731 82

The placental trophoblast at different stages of pregnancy contains some drug transporters and xenobiotic-metabolising enzymes, as well as ligand-activated nuclear receptors, which control their inducible transcriptional regulation. Glucocorticoid receptor alpha (GRalpha) is expressed in both placental syncytiotrophoblast and cytotrophoblast. GRalpha was shown to control inducible expression of several enzymes of the cytochrome P-450 family (CYP) and the drug transporter P-glycoprotein in the liver. However, GRalpha-mediated transcriptional regulation of drug transporters and CYPs has not been studied in the placental trophoblast. In this study, we examined the expression and activity of GRalpha in the transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 in placental trophoblast cell lines. Employing RT-PCR, Western blotting, and luciferase gene reporter assay, we detected the expression and activity of GRalpha in JEG3 and BeWo cell lines. However, we observed that only MDR1 mRNA was up-regulated after treatment of placental cells with dexamethasone. Accordingly, only the promoter of the MDR1 gene was activated by dexamethasone in gene reporter assays in placental cells and the activation was abolished by RU486, an antagonist of GRalpha. CYP3A4 and CYP2C9 promoters were activated in placental cells only after co-transfection with hepatocyte nuclear factor 4alpha (HNF4alpha), which indicates the hepatocyte-specific character of GRalpha-mediated regulation of the genes. On the other hand, coexpression of HNF4alpha had no effect on the activation of the MDR1 gene promoter, suggesting HNF4alpha-independent regulation via GRalpha. We conclude that GRalpha may be involved in the transcriptional regulation of P-glycoprotein in the placental trophoblast. We also indicate that the CYP3A4 and CYP2C9 genes are not inducible through GRalpha in placental cell lines, due to the lack of HNF4alpha expression and possibly some additional hepatocyte-specific transcriptional factors.
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PMID:Examination of Glucocorticoid receptor alpha-mediated transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 genes in placental trophoblast cell lines. 1757 86


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