Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether human liver responds to treatment with aromatic hydrocarbons (AHs) with induction of the multidrug resistance (mdr) gene product P-glycoprotein and whether AH induction of mdr involves the Ah receptor, we compared induction of mdr mRNA with induction of cytochrome P450 (CYP)1A1 mRNA in AH-treated cultures of primary human hepatocytes. Hepatocytes from all 15 individuals tested responded to treatment with 3-methylcholanthrene (MC) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with induction of CYP1A1 mRNA. However, only 62% and 55% of the preparations responded to treatment with MC and TCDD, respectively, with induction of mdr mRNA. Indeed, in some individuals mdr mRNA was suppressed by MC and TCDD despite robust CYP1A1 induction. These studies provide the first evidence that not only does individual variation in mdr induction by AH exist but that AHs regulate mdr in humans by a novel mechanism distinguishable from the classical Ah receptor pathway. The dramatic variability in AH induction of mdr may be a predictive risk factor that will help to identify an individual's risk of AH-associated toxicities.
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PMID:Phenotypic variability in induction of P-glycoprotein mRNA by aromatic hydrocarbons in primary human hepatocytes. 766 17

P-Glycoprotein the multidrug resistance (mdr) efflux transporter is encoded by class 1 mdr genes (mdr1) in humans and rodent species. In rat liver and in rat hepatocytes in primary culture, expression of mdr1 genes can be induced with the carcinogenic aromatic amine 2-acetylaminofluorene (2-AAF). As a consequence, increased P-glycoprotein levels led to an accelerated efflux of vinblastine from the hepatocytes and to resistance towards vinblastine-mediated cytotoxicity. N-Hydroxylation, an obligatory initial step in the activation of 2-AAF into electrophilic DNA-binding metabolites is catalyzed predominantly by cytochrome P450 (CYP)1A2, an isozyme present in normal rat liver. In rat hepatocytes in primary culture, mdr1 induction with 2-AAF could be inhibited by addition of the CYP1A-inhibitor alpha-naphthoflavone, indicating the requirement for metabolic conversion of 2-AAF to act as an inducer of mdr1 gene expression. Both N-hydroxy-2-AAF and the mutagenic 2-AAF derivative N-acetoxy-2-AAF (AAAF) were more potent than 2-AAF as mdr1 inducers. mdr1 induction also decreased when deacetylation of AAAF, which strongly accelerates its conversion into a mutagen, was inhibited with paraoxon. Furthermore, rat liver epithelial cells stably transfected with mouse CYP1A2 showed inducibility of mdr1 gene expression with 2-AAF, whereas the parental cell line, which is devoid of CYP1A2 activity, did not. These findings indicate that electrophilic metabolites formed during 2-AAF or AAAF metabolism are responsible for mdr1 induction in rat hepatocytes. The increased mdr1 gene expression may reflect an adaptive cellular response to electrophiles which includes enhanced synthesis of P-glycoprotein aimed to protect the cell from further damage.
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PMID:Metabolic activation of 2-acetylaminofluorene is required for induction of multidrug resistance gene expression in rat liver cells. 795 3

P-glycoproteins encoded by the (multi-drug resistance) mdr genes play a central role in the resistance of tumor cells to a wide range of anti-cancer drugs. Modulation of P-glycoprotein function could therefore provide a means of sensitising tumor cells to chemotherapy. Studies in this context have centred around the use of compounds which antagonise the P-glycoprotein membrane transport system. To investigate the possibility of modulating P-glycoprotein expression at a transcriptional level, we investigated the effects of hormonal factors and cytochrome P450-inducing agents on hepatic expression of murine mdr 1, mdr 2 and mdr 3. Hepatic mdr 2 and mdr 3 expressions were significantly suppressed in hypophysectomised animals, indicating that pituitary hormones activate the hepatic expression of these genes. Many of the foreign compounds and anti-cancer drugs tested did not significantly induce mdr 1, 2 or 3 expression. However, it was of particular interest that a potent cytochrome P450 inducer, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, almost completely suppressed hepatic mdr 2 and 3 expressions.
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PMID:Suppression of multi-drug resistance gene expression in the mouse liver by 1,4-bis[2,(3,5-dichloropyridyloxy)]benzene. 805 51

Colchicine is widely used in the treatment of acute goutty arthritis. Recently, colchicine was shown to be effective in inflammatory diseases such as familial Mediterranean fever. Two proteins can modulate its pharmacokinetics: tubulin, the specific intracellular receptor for colchicine which determines the plasma half-life, and P-glycoprotein, an active efflux pump towards some anticancer drugs which regulates colchicine absorption, distribution, and elimination. Therapeutic dosage is monitored empirically, by the control of the balance between the occurrence of side effects and the clinical efficacy. Recently, using a specific and sensitive radioimmunoassay, the investigation of plasma concentrations during single and multiple dose studies has allowed to define the colchicine pharmacokinetic parameters. Following oral route, colchicine bioavailability is extremely variable (from 24 to 88% of the administered dose), the distribution volume is elevated (7 l/kg) but the binding to albumin is moderate. Colchicine elimination occurred mainly via hepatic pathways and the elimination half-life ranged from 20 to 40 hours. In multiple dose study (1 mg/d), the steady-state is reached 8 days after the first oral administration and plasma concentrations ranged from 0.3 to 2.5 ng/ml. Pharmacokinetic/pharmacodynamic studies show that the biological effects of colchicine were not related to plasma concentrations but with intraleukocyte concentrations. Drug interactions may occur when colchicine is associated to drugs which interact with cytochrome P450 and/or P-glycoprotein and modify renal and/or hepatic clearances. The therapeutic drug monitoring of colchicine during these circumstances could allow to prevent the observation of side effects.
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PMID:[Colchicine: recent data on pharmacokinetics and clinical pharmacology]. 852 61

Retinoic acid (RA) regulates the differentiation and proliferation of a wide variety of different cell types and all-trans RA induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). However, clinical resistance to retinoids may develop and poses a serious problem for differentiation-inducing therapy. We studied the effects of RA in combination with a cytochrome P450 inhibitor (clotrimazole) and a P-glycoprotein antagonist (verapamil) on cell growth and differentiation of RA-resistant HL-60 cells and fresh RA-resistant leukemic cells from two APL patients. RA-resistant HL-60 cells and APL cells differentiated to mature granulocytes when cultured with all-trans RA and either clotrimazole and verapamil but not with either of the agents alone. These findings were confirmed in these cells by their increased expression of CD11b antigen and migration-inhibitory factor-related protein-8/14 mRNAs and decreased levels of c-myc mRNA. These combinations also markedly decreased the number of viable cells and inhibited cellular proliferation. After isolation of microsomes, measurements showed that levels of cytochrome P450 activities in both wild-type and RA-resistant HL-60 cells were almost comparable. Moreover, expression of the CYP1A1-type cytochrome P450 gene could not be detected in either cell type. However, RA-resistant HL-60 cells and APL cells, but not RA-sensitive HL-60 cells and APL cells, expressed multidrug-resistance-1 gene transcripts. Taken together, acquired resistance to RA may be explained in part by drug metabolism in leukemic cells. Possible mechanisms for accelerated clearance of RA include the induction of non-CYP1A1 cytochrome P450 enzymes and P-glycoprotein.
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PMID:Mechanisms of retinoid resistance in leukemic cells: possible role of cytochrome P450 and P-glycoprotein. 855 97

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized. 2. Specific cytochrome P450 (CYP) enzymes have been recently shown to be involved in the metabolism of several essential anticancer agents. In particular, enzymes of the CYP3A subfamily play a role in the metabolism of many anticancer drugs, including epipodophyllotoxins, ifosphamide, tamoxifen, taxol and vinca alkaloids. CYP3A4 has been shown to catalyse the activation of the prodrug ifosphamide, raising the possibility that ifosphamide could be activated in tumour tissues containing this enzyme. 3. As examples of recently found, clinically significant interactions, cyclosporin considerably increases plasma doxorubicin and etoposide concentrations. Although cyclosporin and calcium channel blockers may influence the pharmacokinetics of certain anticancer agents by inhibiting their CYP3A mediated metabolism, it is more likely that these P-glycoprotein inhibitors inhibit P-glycoprotein mediated drug elimination. 4. Appropriate caution should be exercised when combining P-glycoprotein inhibitors and potential CYP3A inhibitors with cancer chemotherapy.
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PMID:The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. 870 57

Until the late eighties, clinical resistance to azole antifungals was a rare phenomenon. Only a few cases of resistance to ketoconazole were found in patients with chronic mucocutaneous candidiasis (CMC). The spread of AIDS and the widespread prophylactic and therapeutic use of the hydrophilic azole compound fluconazole resulted both in the selection and induction of resistant strains and in a shift in the nature of the infecting organisms. Most azole antifungals such as itraconazole, ketoconazole and fluconazole are active against a variety of fungal diseases. However, the concentration needed to inhibit growth is dependent on the nature of the infecting species. Mucor spp., e.g., are almost insensitive to present available azole compounds and can be regarded as intrinsically resistant to azole treatment. Physiochemical features, such as the hydrophobicity and pKa, of a given azole, define whether or not it will be active or cross-resistant against a given species. Fluconazole is almost inactive against Candida krusei and Aspergillus fumigatus, whereas the lipophilic itraconazole is active against these species. A third type of resistance is acquired or induced resistance. This is the most controversial type because, even within a given species, organisms may differ in their response to the same azole. For these strains, convincing evidence can only be obtained when there is a genotypically related strain, which does not show resistance. In a limited number of biochemical or molecular biological studies the mechanisms of resistance have been investigated at the molecular level. These studies show that resistance can occur when there is an insufficient intracellular content of the azole. This can be due to impermeability problems, inactivated uptake systems or, and more likely, the presence of active multidrug resistance gene products of the P-glycoprotein type. Alteration or overexpression of the target for azole antifungals, the cytochrome P450-dependent 14 alpha-demethylase, also induces resistance. The nature and amount of the accumulating sterols also are of great importance for azole-induced growth inhibition. This may explain why mutations in other enzymes of the ergosterol biosynthesis pathway, e.g. the delta 5-6 desaturase, can contribute to azole resistance.
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PMID:Mechanisms of resistance to azole antifungals. 885 41

Agents (modulators) that reverse the in vitro resistance of tumor cells to anticancer drugs that are substrates for P-glycoprotein (Pgp, the product of the MDR1 gene) have been given to patients concurrently with anticancer drugs in an attempt to improve therapeutic response. The vast majority of investigations into these drugs indicate that Pgp modulators decrease the systemic clearance of anticancer drugs, thus potentially nonselectively increasing exposure to normal and malignant cells and thereby potentially increasing the severity and/or incidence of adverse effects associated with the anticancer therapy. Mechanisms by which Pgp modulators could alter the pharmacokinetics of the anticancer agent include competition for cytochrome P450 intestinal or liver metabolism, inhibition of Pgp-mediated biliary excretion or intestinal transport, or inhibition of renal elimination. It is suggested that administration of Pgp modulators is unlikely to improve the therapeutic index for anticancer drugs unless agents that lack significant pharmacokinetic interactions are found. Moreover, it will likely be required that there be some cancer-tissue selectivity for modulators in order to avoid collaterally increasing the sensitivity of normal Pgp-expressing tissues to the anticancer drug.
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PMID:Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs? 885 49

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

The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.
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PMID:Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression. 915 65


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