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)

The human colon carcinoma cell line, Caco-2, is widely used as a model for oral absorption of xenobiotics. The usefulness of Caco-2 cells has been limited, however, because they do not express appreciable quantities of CYP3A4, the principle cytochrome P450 present in human small bowel epithelial cells. We report that treatment of Caco-2 cells with 1 alpha,25-dihydroxyvitamin D3, beginning at confluence, results in a dose- and duration-dependent increase in CYP3A4 mRNA and protein, with little apparent effect on the expression of CYP3A5 or CYP3A7. This treatment also results in increases in NADPH cytochrome P450 reductase and P-glycoprotein (the MDR1 gene product) but has no detectable effect on expression of CYP1A1, CYP2D6, cytochrome b5, liver or intestinal fatty acid binding proteins, or villin. Maximal expression of CYP3A4 requires an extracellular matrix on a permeable support and the presence of serum. In the treated cells, the intrinsic formation clearance of 1'-hydroxymidazolam (a reaction characteristically catalyzed by CYP3A enzymes) was estimated to be somewhat lower than that of human jejunal mucosa (1.14 and 3.67 ml/min/g of cells, respectively). The 1'-OH-midazolam/4-OH-midazolam product ratio produced by the cells (approximately 5.3) is comparable to, but somewhat lower than, that observed in human jejunal microsomes (7.4-15.4), which may reflect the presence of CYP3A7 in the Caco-2 cells. 25-Hydroxyvitamin D3 is less efficacious but reproduces the effects of the dihydroxy compound, whereas unhydroxylated vitamin D is without appreciable effect. These observations, together with the time course of response, suggest that the vitamin D receptor may be involved in CYP3A4 regulation. The culture model we describe should prove useful in defining the role of CYP3A4 in limiting the oral bioavailability of many xenobiotics.
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PMID:Expression of enzymatically active CYP3A4 by Caco-2 cells grown on extracellular matrix-coated permeable supports in the presence of 1alpha,25-dihydroxyvitamin D3. 914 12

Caco-2 cells grown in the presence of 1alpha,25-di-OH vitamin D(3) (di-OH vit D(3)) were used as a model to evaluate the effects of P-glycoprotein (Pgp) efflux on CYP3A4-mediated metabolism of indinavir during intestinal absorption. Caco-2 cells grown under these conditions demonstrated significant CYP3A4 activity and maintained Pgp-mediated directional transport of indinavir. Metabolism of indinavir in the di-OH vit D(3)-treated cells correlated with the level of CYP3A activity and generated metabolites consistent with CYP3A4-mediated metabolism. During transport experiments, indinavir metabolites are selectively secreted into the apical compartment, consistent with Pgp-mediated efflux. Using formation of the most abundant metabolite, M6, as a marker for indinavir metabolism, we observed that the extent of indinavir metabolism is not significantly affected by the direction of indinavir transport or by inhibition of Pgp with cyclosporin A. However, because Pgp efflux results in higher indinavir transport in the basolateral-to-apical direction than in the apical-to-basolateral direction, the ratio of M6 produced normalized to the amount of drug transported across the monolayer was higher for apical-to-basolateral transport. Thus, Pgp efflux in a direction opposite to absorptive transport results in more metabolite produced per mole of drug that is absorbed. In summary, the results support a role of Pgp in increasing intestinal presystemic metabolism and in removal of CYP3A4-generated metabolites from the intracellular compartment.
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PMID:Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. 1060 64

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

D-alpha-tocopheryl polyethylene glycol succinate (TPGS) has been utilized in numerous drug delivery formulations in recent years. Because of its amphiphilic structure, it can be used as emulsifier and vehicle for lipid-based drug delivery formulations. It is also an effective P-glycoprotein (P-gp) inhibitor. However, TPGS represents only one of the surfactants in the class of "Vitamin-PEG" conjugated surfactants. To design a new adjuvant or additive, a conjugate made of vitamin D (cholecalciferol) and PEG-cholecalciferol polyethylene glycol succinate (CPGS) was synthesized via a two-step reaction. We hypothesized that CPGS may exhibit similar characteristics to TPGS, and thus the physicochemical properties as well as the anticancer properties of CPGS were studied. The results demonstrated that CPGS reduced the particle size and increased the encapsulation efficiency of the PLGA nanoparticles, indicating that CPGS may also have the emulsifier function similar to TPGS. The drug release profiles showed that the nanoparticles with CPGS additive had a lower initial burst and more sustained release pattern. In vitro testing with Caco-2 cells showed that CPGS could increase the cytotoxicity of DOX-loaded PLGA nanoparticles. Based on the rhodamine accumulation study, the increased cytotoxicity is possibly due to the P-gp inhibition by CPGS. From current results, the use of CPGS as an adjuvant is promising and may enhance the efficacy of the overall drug delivery system.
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PMID:Potential use of cholecalciferol polyethylene glycol succinate as a novel pharmaceutical additive. 1764 25

P-glycoprotein, encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter and plays an important role in pharmacokinetics. The expression of MDR1 is induced by a variety of compounds, of which 1alpha,25-dihydroxyvitamin D(3) is known to be an effective inducer. However, it remains unclear how 1alpha,25-dihydroxyvitamin D(3) regulates the expression of MDR1. In this study, we demonstrated that the vitamin D receptor (VDR) induces MDR1 expression in a 1alpha,25-dihydroxyvitamin D(3)-dependent manner. Luciferase assays revealed that the region between -7.9 and -7.8k bp upstream from the transcription start site of the MDR1 is responsible for the induction by 1alpha,25-dihydroxyvitamin D(3). Electrophoretic mobility shift assays revealed that several binding sites for the VDR/retinoid X receptor alpha (RXRalpha) heterodimer are located between the -7880 and -7810 bp region, to which the three molecules of VDR/RXRalpha are able to simultaneously bind with different affinities. Luciferase assays using mutated constructs revealed that the VDR-binding sites of DR3, DR4(I), MdC3, and DR4(III) contribute to the induction, indicating that these binding sites act as vitamin D response elements (VDREs). The contribution of each VDRE to the inducibility was different for each response element. An additive effect of the individual VDREs on induced luciferase activity by 1alpha,25-dihydroxyvitamin D(3) was also observed. These results indicate that the induction of MDR1 by 1alpha,25-dihydroxyvitamin D(3) is mediated by VDR/RXRalpha binding to several VDREs located between -7880 and -7810bp, in which every VDRE additively contributes to the 1alpha,25-dihydroxyvitamin D(3) response.
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PMID:Identification of the functional vitamin D response elements in the human MDR1 gene. 1860 86

Imazalil (IMA) is a widely used imidazole-antifungal pesticide and, therefore, a food contaminant. This compound is also used as a drug (enilconazole). As intestine is the first site of exposure to ingested drugs and pollutants, we have investigated the effects of IMA, at realistic intestinal concentrations, on xenobiotic-metabolizing enzymes and efflux pumps by using Caco-2 cells, as a validated in vitro model of the human intestinal absorptive epithelium. For comparison, other conazole fungicides, i.e. ketoconazole, propiconazole and tebuconazole, were also studied. IMA induced cytochrome P450 (CYP) 1A1 activity to the same extent as benzo(a)pyrene (B(a)P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in a dose- and time-dependent manner. Cell-free aryl hydrocarbon receptor (AhR) binding assay and reporter gene assay suggested that IMA is not an AhR-ligand, implying that IMA-mediated induction should involve an AhR-independent pathway. Moreover, IMA strongly inhibited the CYP3A4 activity in 1,25-vitamin D(3)-induced Caco-2 cells. The other fungicides had weak or nil effects on CYP activities. Study of the apical efflux pump activities revealed that ketoconazole inhibited both P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP-2) or breast cancer resistance protein (BCRP), whereas IMA and other fungicides did not. Our results imply that coingestion of IMA-contaminated food and CYP3A4- or CYP1A1-metabolizable drugs or chemicals could lead to drug bioavailability modulation or toxicological interactions, with possible adverse effects for human health.
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PMID:CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides. 1907 Jun 57

The effects of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] on gene expression and function were studied in Caco-2 cells. Microarray analyses, real-time quantitative polymerase chain reactions, and Western blotting were used to determine the mRNA and protein expression of transporters and enzymes after 1,25(OH)(2)D(3) or vehicle (0.1% ethanol) treatment for 1, 3, 6, and 10 days. The mRNA and protein expressions of the apical sodium-dependent bile acid transporter, oligopeptide transporter 1, multidrug resistance-associated protein (MRP) 3, and sulfotransferase 1E1 remained unchanged with 1,25(OH)(2)D(3) treatment, whereas those for CYP3A4, multidrug resistance protein 1, and MRP2 were significantly increased (P < 0.05). 1,25(OH)(2)D(3) treatment significantly enhanced MRP4 protein expression by increasing protein stability without affecting mRNA expression, as confirmed in cycloheximide experiments. Marked increase in 6beta-hydroxylation of testosterone by CYP3A4 was also observed in the 6-day 1,25(OH)(2)D(3)-treated (100 nM) cell lysate. The transport of [(3)H]digoxin, the P-glycoprotein (P-gp) substrate, after treatment with 100 nM 1,25(OH)(2)D(3) for 3 days revealed a higher apparent permeability (P(app)) value in the basal (B)-to-apical (A) direction over that of vehicle treatment (15.1 +/- 0.53 x 10(-6) versus 11.8 +/- 0.58 x 10(-6) cm/s; P < 0.05), whereas the P(app) in the A-to-B direction was unchanged; the efflux ratio was increased (from 5.8 to 8.0). Reduced cellular retention of 5-(and-6)-carboxy-2',7'-dichlorofluorescein, suggestive of higher MRP2 activity, was observed in the 3-day 100 nM 1,25(OH)(2)D(3)-treated cells over controls. Higher protein expression of CYP3A4, MRP2, P-gp, and MRP4 was also observed after a 6-day treatment with other vitamin D analogs (100 nM 1alpha-hydroxyvitamin D(3),1alpha-hydroxyvitamin D(2) or Hectorol, and 25-hydroxyvitamin D(3)) in Caco-2 cells, suggesting a role of 1,25(OH)(2)D(3) and analogs in the activation of enzymes and transporters via the vitamin D receptor.
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PMID:Up-regulation of transporters and enzymes by the vitamin D receptor ligands, 1alpha,25-dihydroxyvitamin D3 and vitamin D analogs, in the Caco-2 cell monolayer. 1941 24

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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PMID:Glucocorticoid resistance in inflammatory diseases. 1948 16

Glucocorticoids are the mainstay of asthma management and effectively treat acute exacerbations of asthma. However, a small subset of asthmatics, usually with severe asthma, respond poorly even to systemic administration of high-dose glucocorticoids and this condition is termed "steroid-resistant asthma". This cohort, although small, accounts for approximately 50% of total health care cost for asthma. New investigations into the mechanisms of glucocorticoid action have broadened and deepened our understanding of glucocorticoid resistance. Here we review the importance and characteristics of steroid resistant asthma, the mechanisms that mediate the function of glucocorticoids and that lead to the development of this disease and potential therapies to reverse resistance to treatment. Cellular and molecular factors, receptors and complex signalling pathways have all been implicated. Indeed, based on molecular biological studies, excessive activation of intracellular transcription factors, impaired histone deacetylase, and epigenetic (such as miR-18 and miR-124a) as well as other factors (e.g. vitamin D, P-glycoprotein 170, and macrophage migration inhibitory factor and T helper 17 cells and factors related to innate immunity (such as IFN-gamma and LPS)) may result in glucocorticoid resistance. A thorough understanding of the pathogenesis of steroid resistant asthma will help to develop more efficacious agents for the treatment of the disease.
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PMID:Potential therapeutic targets for steroid-resistant asthma. 2041 45

Over the past 20 years, the toxicological and protective roles of the placental barrier with respect to drug detoxification and transporter-controlled protection of the fetus have been intensively examined. Several cytochrome P450 enzymes are expressed in placental trophoblast at different stages of pregnancy, though only a few of these have functional activity to metabolize xenobiotics. Drug transporters such as P-glycoprotein/MDR1 or breast cancer resistance protein (BCRP) are highly expressed in the placenta, and their functional activities have been demonstrated in the placenta both in vitro and in vivo. In addition, several studies have reported on ligand-activated transcription factors and nuclear receptors referred to as "xenosensors" in the placenta. The xenosensors control transcriptional regulation of both xenobiotic-metabolizing enzymes and drug transporters in different organs. Their ligands include toxic compounds and environmental pollutants, drugs, as well as herbal, dietary or vitamin supplements. Nevertheless, it remains debatable whether the placental barrier adapts to toxic injuries coming either from maternal medication or environmental contamination and whether the placenta contains a mechanism to respond dynamically in protecting the developing fetus. In the present paper, we summarize current knowledge about the activity and expression of major ligand-activated transcriptional mechanisms involved in biotransformation enzymes and transporters regulation in human placenta. In particular, we highlight the emerging roles of aryl hydrocarbon (AHR), vitamin D (VDR), glucocorticoid (GR) and pregnane X (PXR) receptors in that regulation. We show that the placenta constitute a unique metabolizing organ with significant overlap of exogenous and endogenous compounds metabolism controlled by nuclear receptors.
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PMID:Nuclear receptors in regulation of biotransformation enzymes and drug transporters in the placental barrier. 2402 Mar 84


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