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)

Expression of P-glycoprotein (P-gp), a plasma membrane glycoprotein involved in multidrug resistance and encoded by mdr genes, was investigated in nonparenchymal rat liver epithelial (RLE) cells in response to acute exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs). High levels of mdr mRNAs were evidenced by Northern blotting in two independent RLE cell lines after treatment by either 3-methylcholanthrene (MC) or benzo-(a)pyrene. MC-mediated mdr mRNA induction was demonstrated to be dose-dependent; it occurred through enhanced expression of the mdr 1 gene, as indicated by reverse transcriptase-polymerase chain reaction analysis using rat mdr gene-specific primers and paralleled an induction of a 140 kDa P-gp as demonstrated by Western blotting. In addition, MC-induced P-gp appeared to be fully functional because RLE cells exposed to MC displayed enhanced cellular efflux of rhodamine 123, a known P-gp substrate, compared to their untreated counterparts. Analysis of time-course induction revealed that mdr mRNA levels were maximally increased when RLE cells were treated for 48 to 96 hr and returned to low levels after the PAH was removed. In contrast to P-gp, both cytochrome P-450 1A1 and cytochrome P-450 1A2 were not detected after exposure to MC, thus indicating that these liver detoxification pathways are not coordinately regulated with P-gp in RLE cells. In addition, MC-mediated P-gp regulation was not associated with major cellular disturbances such as alteration of protein synthesis and, thereby, differed from the known mdr mRNA induction occurring in response to cycloheximide. Moreover, cotreatment with MC and cycloheximide led to a superinduction of mdr mRNAs, thus suggesting that the effects of the two xenobiotics were, at least partly, additive. In contrast to MC and benzo(a)pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo(e)pyrene were unable to increase P-gp expression. These results indicate that some PAHs can act as potent inducers of P-gp in RLE cells and may be interpreted as an adaptive reaction of these cells in lowering cellular accumulation of toxic drugs, including carcinogens transported by P-gp and, therefore, conferring protection on these compounds.
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PMID:P-glycoprotein induction in rat liver epithelial cells in response to acute 3-methylcholanthrene treatment. 863 83

Recent studies have shown that a high proportion of patients with acute promyelocytic leukemia (APL) achieve complete remission after treatment with all-trans retinoic acid (RA). Nevertheless, despite an initial good response, most patients who received continuous treatment with all-trans RA relapsed and develop RA-resistant disease. The detailed mechanisms for this development of RA resistance by APL cells are still unclear. Several possible mechanisms have been considered to explain in vitro resistance to RA. One obvious explanation is the generation of new mutations in the retinoid receptors. However, UF-1 cells (the first permanent APL cell line with RA-resistant features) had no point mutations in the ligand-binding domain of the RAR-alpha gene. Another potential mechanism for clinical RA resistance is the pharmacologic alteration in the metabolism of all-trans RA. Continuous treatment with all-trans RA in APL is associated with a progressive reduction of the plasma concentrations of RA. Induction of cytochrome P-450, cellular RA-binding protein (CRABP) and P-glycoprotein resulted in lower plasma and cellular levels of active retinoids. Thus, acquired resistance to RA may be explained at least in part by drug metabolism in leukemic cells.
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PMID:Retinoid resistance in leukemic cells. 925 Aug 12

Expression of multidrug resistance (mdr) genes encoding the P-glycoprotein (P-gp) drug efflux pump was analysed in cultured rat liver epithelial cells acutely treated by the DNA-damaging agent methyl methanesulfonate (MMS). Exposure to this alkylating agent used at 30 microg/ml for 12 or 24 h was shown to enhance mdr mRNA levels in rat liver cells without alteration of cell viability. Induction of mdr transcripts occurred through increased expression of the mdr1b gene as indicated by reverse transcriptase-polymerase chain reaction analysis using rat mdr gene-specific primers and was not associated with up-regulation of cytochrome P-450 1A1, thereby suggesting that this detoxifying enzyme and P-gp were not coordinately regulated by MMS. In addition, the DNA-damaging agent was found to enhance in a dose-dependent manner cellular efflux of the P-gp substrate rhodamine 123, which was inhibited by the P-gp inhibitor verapamil, thus providing evidence that exposure to MMS led to increased P-gp-related drug transport in rat liver cells. The up-regulation of functional P-gp expression occurring in MMS-treated liver cells may be interpreted as a part of the cellular response to DNA damage.
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PMID:Induction of multidrug resistance gene expression in rat liver cells in response to acute treatment by the DNA-damaging agent methyl methanesulfonate. 953 88

The effect of cytochrome P-450 3A (CYP3A) substrates (erythromycin, midazolam) and an inhibitor (ketoconazole) on P-glycoprotein-mediated transport was studied in Caco-2, the human colon adenocarcinoma cell line expressing various functions of differentiated intestinal epithelial cells. The involvement of P-glycoprotein in the transport of these drugs was also examined. The basal-to-apical transport of rhodamine 123, a P-glycoprotein substrate, was inhibited by erythromycin, midazolam and ketoconazole, as well as by P-glycoprotein inhibitors such as verapamil. The apical-to-basal transport of rhodamine 123 was increased by these drugs. The transepithelial transport of erythromycin and midazolam, but not of ketoconazole, was much greater from the basal to apical side than from the apical to basal side. The inhibitory effect of verapamil was observed on the basal to apical transport of erythromycin, but not on midazolam and ketoconazole transport. In conclusion, erythromycin, midazolam and ketoconazole could interact with P-glycoprotein-mediated transport, and P-glycoprotein could be, at least in part, involved in the transport of erythromycin, but not of midazolam and ketoconazole, in the intestinal epithelia.
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PMID:Interaction with P-glycoprotein and transport of erythromycin, midazolam and ketoconazole in Caco-2 cells. 982 96

Effects of cytochrome P-450 3A- and P-glycoprotein (P-gp)-related compounds, erythromycin, midazolam, ketoconazole, verapamil, and quinidine, on transport of rhodamine 123 (Rho-123), a P-gp substrate, were studied in rat intestine and in Caco-2 cells. Ileum was mainly used in rat studies because this segment showed greater P-gp-mediated Rho-123 transport. In an in vitro everted rat ileum, all the compounds examined significantly inhibited the transport of Rho-123 from serosal to mucosal surfaces across the intestine, with different inhibitory potencies among these compounds. In an in vivo rat study, the exsorption of Rho-123 from blood to the intestinal lumen, which was evaluated as exsorption clearance of Rho-123 under a steady-state plasma concentration of Rho-123, was also inhibited when these compounds were added to the intestinal lumen. Similarly, transepithelial transport of Rho-123 from the basolateral to apical side across Caco-2 cell monolayers was inhibited by these compounds. A linear relationship was observed in their inhibitory potencies on Rho-123 transport between in vitro and in vivo studies using rat ileum and between studies with rat ileum and Caco-2 cells. P-gp-mediated transport across the intestine was found to be inhibited not only by P-gp-related but also by all the cytochrome P-450 3A-related compounds examined. Within experimental error, the relative inhibitory potencies were the same between the studies with rat ileum (in vivo, in vitro) and those with Caco-2 cells. Thus, it is suggested that the function of P-gp and its sensitivity to these drugs may be similar in rat intestine and Caco-2 cells.
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PMID:Transport of rhodamine 123, a P-glycoprotein substrate, across rat intestine and Caco-2 cell monolayers in the presence of cytochrome P-450 3A-related compounds. 1008 98

We studied the effects of two P-glycoprotein (P-gp) inducers, 2-acetylaminofluorene (2-AAF) and phenothiazine (PTZ), administered intraperitoneally, on the activities and content of hepatic cytochrome P-450 (CYP) subfamilies in hepatic microsomes of Sprague-Dawley rats. After 4-day administration of 2-AAF or PTZ, the P-gp content was increased. The total CYP content after PTZ treatment was significantly increased compared with that of controls. The CYP1A, CYP2B and CYP3A2 contents were induced, while the CYP2C6, CYP2C11 and CYP2E1 contents remained unaffected. A marked increase in CYP1A1 was found after administration of each compound. Ethoxyresorufin O-deethylase, pentoxyresorufin O-deethylase, and testosterone 6beta hydroxylation activities showed a significant increase after both 2-AAF and PTZ treatments. In particular, ethoxyresorufin O-deethylase exhibited more than ten times greater activity than that of the controls after the treatments. These results suggest that P-gp inducers affect several CYP subfamilies in addition to CYP3A, which is reported to be up-regulated coordinately with P-gp by a CYP3A inducer.
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PMID:Multiple cytochrome P-450 subfamilies are co-induced with P-glycoprotein by both phenothiazine and 2-acetylaminofluorene in rats. 1037 76

Overexpression of ATP-dependent drug efflux pumps, P-glycoprotein (Pgp) or multidrug resistance-associated protein (MRP), confers multidrug resistance to tumor cells. Modulators of multidrug resistance block the action of these pumps, thereby sensitizing cells to oncolytics. A potent Pgp modulator is LY335979, which fully sensitizes Pgp-expressing cells at 0.1 microM in cytotoxicity assays and for which Pgp has an affinity of 59 nM. The present study examines its effect on MRP1-mediated drug resistance and cytochrome P-450 (CYP) activity and its ability to serve as a Pgp substrate. Drug resistance was examined with HL60/ADR and MRP1-transfected HeLa-T5 cells. Drug cytotoxicity was unaffected by 1 microM LY335979; leukotriene C4 uptake into HeLa-T5 membrane vesicles was unaffected. Because the substrate specificity of Pgp and CYP3A overlap, the effect of LY335979 on the 1'-hydroxylation of midazolam by CYP3A in human liver microsomes was examined. The apparent K(i) was 3.8 microM, approximately 60-fold higher than the affinity of Pgp for LY335979. The modulator's effect on Pgp was evaluated with Pgp-overexpressing CEM/vinblastine (VLB)(100) and parental CCRF-CEM cells. Both cell lines accumulated [(3)H]LY335979 equally well and did not efflux [(3)H]LY335979 during a 3-h incubation, indicating that it is not a substrate of Pgp. Equilibrium-binding studies with CEM/VLB(100) plasma membranes and [(3)H]LY335979 showed that Pgp had a K(d) of 73 nM, which is in good agreement with the previously determined K(i) value. Thus, LY335979 is an extremely potent Pgp, and not MRP1 or MRP2, modulator and has a significantly lower affinity for CYP3A than for Pgp.
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PMID:Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. 1041 2

Many P-glycoprotein (P-gp) inhibitors studied in vitro and in vivo are also known or suspected to be substrates and/or inhibitors of cytochrome P-450 3A (CYP3A). Such overlap raises the question of whether CYP3A inhibition is an intrinsic characteristic of P-gp inhibitors, a matter of concern in the development and rational use of such agents. Thus, the purpose of the present study was to determine whether the ability to inhibit P-gp and CYP3A is, in fact, linked and whether specific P-gp inhibitors with limited ability to inhibit CYP3A can be identified. Therefore, the potency of a series of 14 P-gp inhibitors was assessed by measuring their inhibition of the transepithelial flux across Caco-2 cells of digoxin, a prototypical P-gp substrate. CYP3A inhibition was determined from the impairment of nifedipine oxidation by human liver microsomes. Determination of the apparent Ki values for CYP3A inhibition and the IC50s for P-gp and CYP3A inhibition allowed comparison of the relative inhibitory potency of the compounds on the two proteins' function. The IC50s for P-gp inhibition ranged from 0.04 to 3.8 microM. All compounds inhibited CYP3A with apparent Ki values of between 0.3 and 76 microM and IC50s between 1.5 and 50 microM. However, no correlation was found between the extent of P-gp inhibition and CYP3A inhibition, and the ratio of the IC50 for CYP3A inhibition to the IC50 for P-gp inhibition varied from 1.1 to 125. These results demonstrate that, although many P-gp inhibitors are potent inhibitors of CYP3A, a varying degree of selectivity is present. The development and use of P-gp inhibitors with minimal or absent CYP3A inhibitory effects should decrease the impact of drug interactions on the therapeutic use of such compounds.
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PMID:P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. 1046 89

Grapefruit juice, a beverage consumed in large quantities by the general population, is an inhibitor of the intestinal cytochrome P-450 3A4 system, which is responsible for the first-pass metabolism of many medications. Through the inhibition of this enzyme system, grapefruit juice interacts with a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. In the case of some drugs, these increased drug concentrations have been associated with an increased frequency of dose-dependent adverse effects. The P-glycoprotein pump, located in the brush border of the intestinal wall, also transports many cytochrome P-450 3A4 substrates, and this transporter also may be affected by grapefruit juice. This review discusses the proposed mechanisms of action and the medications involved in drug-grapefruit juice interactions and addresses the clinical implications of these interactions.
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PMID:Drug-grapefruit juice interactions. 1099 29

Understanding the development of a scientific approach is a valuable exercise in gauging the potential directions the process could take in the future. The relatively short history of applying computational methods to absorption, distribution, metabolism and excretion (ADME) can be split into defined periods. The first began in the 1960s and continued through the 1970s with the work of Corwin Hansch et al. Their models utilized small sets of in vivo ADME data. The second era from the 1980s through 1990s witnessed the widespread incorporation of in vitro approaches as surrogates of in vivo ADME studies. These approaches fostered the initiation and increase in interpretable computational ADME models available in the literature. The third era is the present were there are many literature data sets derived from in vitro data for absorption, drug-drug interactions (DDI), drug transporters and efflux pumps [P-glycoprotein (P-gp), MRP], intrinsic clearance and brain penetration, which can theoretically be used to predict the situation in vivo in humans. Combinatorial synthesis, high throughput screening and computational approaches have emerged as a result of continual pressure on pharmaceutical companies to accelerate drug discovery while decreasing drug development costs. The goal has become to reduce the drop-out rate of drug candidates in the latter, most expensive stages of drug development. This is accomplished by increasing the failure rate of candidate compounds in the preclinical stages and increasing the speed of nomination of likely clinical candidates. The industry now understands the reasons for clinical failure other than efficacy are mainly related to pharmacokinetics and toxicity. The late 1990s saw significant company investment in ADME and drug safety departments to assess properties such as metabolic stability, cytochrome P-450 inhibition, absorption and genotoxicity earlier in the drug discovery paradigm. The next logical step in this process is the evaluation of higher throughput data to determine if computational (in silico) models can be constructed and validated from it. Such models would allow an exponential increase in the number of compounds screened virtually for ADME parameters. A number of researchers have started to utilize in silico, in vitro and in vivo approaches in parallel to address intestinal permeability and cytochrome P-450-mediated DDI. This review will assess how computational approaches for ADME parameters have evolved and how they are likely to progress.
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PMID:Progress in predicting human ADME parameters in silico. 1127 94


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