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 multiple drug resistance (MDR) gene has been used as a selectable marker to increase the proportion of bone marrow cells that contain and express this gene by drug selection. By constructing retroviral vectors containing and expressing the MDR gene and a nonselectable gene such as the beta-globin gene, enrichment for cells containing both of these genes can be achieved. A retroviral construct containing MDR cDNA in a Harvey virus-based vector has been used to transfect our ecotropic 3T3 retroviral packaging line GP+E86. Clones have been isolated by exposure of the retrovirally transfected cells (MDR producer cells) to colchicine (60 ng/ml), a selective agent that kills MDR-negative cells. Flow cytometry analysis (fluorescence-activated cell sorting) with an antibody to MDR demonstrates expression of human MDR protein on the surface of these colchicine-resistant producer clones. Untransfected GP+E86 cells are negative. Colchicine-resistant clones were titered using clone supernatants and the highest titer clone (4 x 10(4) viral particles per ml) was cocultured with 10(6) donor mouse bone marrow cells for 24-48 hr. The donor cells were then injected into congenic irradiated mice, and the presence of the MDR gene was assayed by the polymerase chain reaction (PCR) analysis using MDR-specific primers. In one experiment eight of nine transduced mice were positive for MDR by PCR of peripheral blood 14 and 50 days posttransplantation; after 240 days three of nine transduced mice were positive. Bone marrow obtained from one of these positive animals was stained with the MDR monoclonal antibody and the granulocyte population was analyzed by FACS. Approximately 14% of the total granulocyte pool contain increased levels of MDR protein. In addition, the bone marrow cells of several mice initially positive for MDR gene by PCR, and subsequently negative, were exposed to taxol, a drug whose detoxification depends on MDR gene expression; a positive signal was obtained in all of these mice, indicating drug selection of MDR-positive marrow cells. Cell sorting studies of these mice also show an increased number of high-MDR-expressing marrow cells, selected after exposure to taxol. Thus, in this live animal model MDR transduction is effective in selecting a human MDR-expressing population of marrow cells resistant to taxol chemotherapy. This strategy may, thus, be useful in humans to prevent the marrow toxicity induced by anticancer agents such as taxol and as a selectable marker to enrich for cells simultaneously transduced with a nonselectable gene.
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PMID:Transfer and expression of the human multiple drug resistance gene into live mice. 135 67

Two photoactive radiolabeled analogs of colchicine, N-(p-azido[3,5-[3H]benzoyl)aminohexanoyldeacetylcolchicine ([3H]NABC]) and N-(p-azido-[3-125I]salicyl)aminohexanoyldeacetylcolchicine ([125I]NASC) were synthesized and used to identify colchicine-specific acceptor(s) in membrane vesicles from multidrug resistant (MDR) variant DC-3F/VCRd-5L Chinese hamster lung cells. Both [3H]NABC and [125I]NASC specifically photolabeled a prominent 150-180 kDa polypeptide in membrane vesicles from DC-3F/VCRd-5L cells. The photolabeled polypeptide was immunoprecipitated by monoclonal antibody C219 specific for the MDR-related P-glycoprotein (P-gp) indicating the identity of this protein with P-gp. Colchicine at 1000 microM reduced [3H]NABC photolabeling of P-gp by 72%. Furthermore, 100 microM of colchicine, vincristine, vinblastine, doxorubicin and actinomycin D inhibited [125I]NASC photolabeling by 45, 88.8, 91.1, 61.5, and 51% respectively. However, methotrexate did not affect the [125I]NASC photolabeling of P-gp, indicating the multidrug specificity of the P-gp colchicine acceptor for drugs to which these cells are resistant.
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PMID:Photoaffinity labeling of P-glycoprotein in multidrug resistant cells with photoactive analogs of colchicine. 256 69

Colchicine and doxorubicin are secreted into bile as a major pathway of their elimination. Colchicine and doxorubicin are also substrates for P-glycoprotein, and P-glycoprotein has been demonstrated to be present at the liver canalicular membrane. Cyclosporin (CsA) inhibits colchicine biliary secretion in vivo. In the present study, the effects of SDZ PSC-833, a nonimmunosuppressive cyclosporin D analog, on the biliary secretion of colchicine and doxorubicin were investigated. SDZ PSC-833 given at a bolus dose of 2 mg/kg promptly decreased colchicine biliary clearance from 9.05 +/- 0.2 to 2.41 +/- 0.43 ml min-1 kg-1 (P < 0.001) and the colchicine bile/plasma ratio from 146 +/- 8 to 35 +/- 5 (P < 0.001). SDZ PSC-833 also inhibited doxorubicin biliary clearance (basal: 10.5 +/- 3 vs post-SDZ PSC-833: 2.48 +/- 0.94 ml min-1 kg-1; P = 0.06) and the doxorubicin bile/plasma ratio (basal: 228 +/- 64 vs post-SDZ PSC-833: 48 +/- 22; P < 0.01). Colchicine renal secretion was completely inhibited by SDZ PSC-833. Thus, SDZ PSC-833 inhibits the constitutive transport of the multi-drug-resistance substrates colchicine and doxorubicin and is more potent than cyclosporin in this regard. The possibility of increased toxicity to normal tissues because of impaired elimination of cytotoxic agents will need to be considered if SDZ PSC-833 is used to chemosensitize cancer cells.
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PMID:Effect of the nonimmunosuppressive cyclosporin analog SDZ PSC-833 on colchicine and doxorubicin biliary secretion by the rat in vivo. 791 Jul 87

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

Classically, drug penetration through the blood-brain barrier depends on the lipid solubility of the substance, except for some highly lipophilic drugs, like colchicine and vinblastine, both substrates of P-glycoprotein, a drug efflux pump present at the luminal surface of the brain capillary endothelial cells. Colchicine and vinblastine uptake into the brain was studied in the rat using the in situ brain perfusion technique and two inhibitors of P-glycoprotein, verapamil and SDZ PSC-833. When rats were pretreated with PSC-833 (10 mg/kg, intravenous bolus), colchicine and vinblastine uptake was enhanced 8.42- and 9.08-fold, respectively, in all the gray areas of the rat brain studied. The mean colchicine distribution volume was increased from 0.67 +/- 0.41 to 5.64 +/- 0.70 microliters/g and vinblastine distribution volume from 2.74 +/- 1.15 to 24.88 +/- 4.03 microliters/g. When rats were pretreated with verapamil (1 mg/kg, intravenous bolus), colchicine distribution volume was increased 3.70-fold. The increase in colchicine and vinblastine did not differ between the eight brain gray areas. PSC-833 and verapamil pretreatment had no influence on the distribution volume of either drug in the choroid plexus. Nevertheless, distribution volumes remained small, considering the highly lipophilic nature of the substances. We suggest that P-glycoprotein is either only partially inhibited (difficulty of fully saturating P-glycoprotein, especially under in vivo conditions) or not the only barrier to these two drugs.
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PMID:Role of P-glycoprotein in the blood-brain transport of colchicine and vinblastine. 885 54

1. Colchicine poisoning, which is relatively rare, is associated with significant morbidity and mortality. Whilst a new treatment modality, in the form of colchicine-specific Fab fragments is on the horizon, currently available therapy is largely supportive. 2. The elimination of colchicine occurs primarily by hepatic metabolism, following a first-order process, with significant enterohepatic circulation. Renal extraction is responsible for approximately 20% of colchicine elimination. 3. We report a case of colchicine intoxication, complicated by the presence of co-ingestants, in which serum colchicine concentrations remained quasi-constant over the 3 days of the patient's survival, consistent with marked alterations both in metabolism and excretion. The initial presentation was relatively benign but the subsequent course was one of severe colchicine poisoning, resulting in death. 4. Severe colchicine toxicity appears to have resulted in a vicious cycle of progressive organ dysfunction and impaired elimination. 5. Josamycin, one of the co-ingestants and an inhibitor of P-glycoprotein, the membrane pump responsible for multidrug resistance, may have played a significant role in impeding the cellular and biliary elimination of colchicine. Co-ingested opioid and anticholinergic compounds may have altered colchicine absorption and gastrointestinal transit. 6. This case serves as a reminder of the need for attention to co-ingested drugs, to early aggressive therapy, and if available, to consideration of immunotherapy.
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PMID:Markedly altered colchicine kinetics in a fatal intoxication: examination of contributing factors. 893 83

To study the role of P-glycoprotein (P-gp) in the delivery of colchicine from blood to brain, the pharmacokinetics of colchicine in plasma and brain was studied in the rat by an in vivo method and by the in situ brain perfusion technique. Colchicine was administered intravenously at three doses (1, 2.5, and 5 mg/kg) with or without an inhibitor of P-gp, verapamil (0.5 mg/kg i.v.); blood and brain samples were taken at t = 1, 2, and 3 hr. Areas under the colchicine curve at doses from 2.5 to 5 mg/kg were proportional to dose for plasma but not for brain. At a colchicine dose of 5 mg/kg, verapamil co-treated rats showed a 1.65-fold enhancement of the colchicine concentration in plasma but a 4.5-fold enhancement in brain. During short experimental times (in situ brain perfusion technique), a comparable enhancement was found (4.26-fold): mean distribution volumes of colchicine were enhanced from 0.23 +/- 0.17 to 0.98 +/- 0.19 microl/g for the eight gray areas, and no effect was observed in the choroid plexus, which do not express P-gp. These results clearly show that P-gp, present at the luminal surface of the capillary endothelial cells, is responsible for the weak penetration of colchicine into the brain.
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PMID:Role of P-170 glycoprotein in colchicine brain uptake. 921 92

In this paper, we show that P-glycoprotein contains two distinct sites for drug binding and transport, and that, unexpectedly, these sites interact in a positively cooperative manner. The kinetics of transport of rhodamine 123 and Hoechst 33342 in isolated P-glycoprotein-rich plasma membrane vesicles from Chinese hamster ovary CH(R)B30 cells were followed by continuous fluorescence monitoring. Each substrate stimulated P-glycoprotein-mediated transport of the other. Colchicine and quercetin stimulated rhodamine 123 transport and inhibited Hoechst 33342 transport. In contrast, anthracyclines such as daunorubicin and doxorubicin stimulated Hoechst 33342 transport and inhibited rhodamine 123 transport. Vinblastine, actinomycin D, and etoposide inhibited transport of both dyes. The results are consistent with a functional model of P-glycoprotein containing at least two positively cooperative sites (H site and R site) for drug binding and transport. This model is consistent with earlier observations of competitive and non-competitive effects of P-glycoprotein substrates and chemosensitizers. Such a two-site model may be fundamental to multidrug transport by P-glycoprotein, and it may be a feature common to other ATP-dependent transporters belonging to the ATP-binding cassette superfamily.
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PMID:Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. 943

A simultaneous brain and blood microdialysis system was developed to study the passage of colchicine through the blood-brain barrier in the mouse. Colchicine was administered as a bolus in the jugular vein (1.5 mg kg-1) and its hippocampal extracellular fluid (ECF) and blood kinetics were determined over a 4 h period using two microdialysis probes, one in the dorsal hippocampus, the other in the inferior vena cava. Colchicine rapidly diffused into the hippocampus (maximum concentration in the first dialysate sample) and brain and blood concentrations declined in parallel, suggesting rapid equilibration between these two compartments. However, only 6. 7% of total blood colchicine, 14% of unbound colchicine was present in the hippocampus suggesting that the P-glycoprotein efflux pump limits colchicine uptake by the brain. We also found, using conventional tissue homogenate analysis in parallel, that the concentration of colchicine in the hippocampal ECF was 10 times less than that in the intracellular space and that the hippocampus colchicine concentration was 2.8 times higher than that of the rest of the brain. This study shows that the simultaneous brain and blood microdialysis can be used to measure the passage of colchicine through the blood-brain barrier and to estimate the brain extra- and intracellular distribution of colchicine.
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PMID:Simultaneous microdialysis in brain and blood of the mouse: extracellular and intracellular brain colchicine disposition. 955 78

Vesicular transport inhibitors have been reported to inhibit biliary excretion of some organic anions, suggesting that vesicular transport has a role in intracellular transport of these compounds. However, these inhibitors are substrates for P-glycoprotein. To examine whether P-glycoprotein has a role in canalicular transport of organic anions in addition to the canalicular multispecific organic anion transporter, we studied the effect of colchicine, a vesicular transport inhibitor, and phenothiazine to increase P-glycoprotein expression on biliary excretion of various organic anions in rats. Colchicine treatment slightly but significantly inhibited biliary excretion of indocyanine green, dinitrophenyl-glutathione and pravastatin, and had no effect on biliary excretion of sulphobromophthalein and dibromosulphophthalein. Phenothiazine treatment did not affect biliary excretion of indocyanine green and pravastatin, but it increased biliary sulphobromophthalein-glutathione excretion. In conclusion, the present findings suggest that P-glycoprotein plays an additive role on biliary excretion of some organic anions in addition to the canalicular multispecific organic anion transporter.
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PMID:Effects of colchicine and phenothiazine on biliary excretion of organic anions in rats. 964 9


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