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

---

Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was to evaluate the influence of glutathione (GSH), the thiomer chitosan-4-thiobutylamidine (chitosan-TBA) and a combination of both compounds on P-glycoprotein (P-gp) activity. Permeation studies were performed with freshly excised guinea pig ileum mounted in Ussing chambers using the fluorescent dye rhodamine-123 (Rho-123) as P-gp substrate. Apparent permeability coefficients (Papp) as well as efflux ratios (secretory Papp/absorptive Papp) were calculated and compared with values gained from experiments with the well-established P-gp inhibitors terfenadine and verapamil. In the presence of terfenadine, verapamil as well as GSH, the absorptive transport of Rho-123 across intestinal tissue increased, while the secretory decreased with efflux ratios around 1.0. Chitosan-TBA and especially chitosan-TBA/GSH not only enhanced absorption of Rho-123, but also reduced the basolateral to apical secretion of Rho-123 resulting in efflux ratios of 1.1, 0.8 and 0.5. The study indicates that chitosan-TBA/GSH is a potentially valuable tool for inhibiting the ATPase activity of P-gp in the intestine.
...
PMID:Glutathione and thiolated chitosan inhibit multidrug resistance P-glycoprotein activity in excised small intestine. 1637 16

Multiple drug resistance (MDR) represents a major obstacle to successful application of chemotherapy and a basic problem in cancer biology. MDR occurs at the cellular level and is multi-factorial in nature. The multidrug resistance gene, MDR1, and its gene product P-glycoprotein (P-gp) are now well known as an important determinant of MDR. Much effort has been devoted to develop P-gp inhibitors to modulate resistance. However, most of these resistance-modifying agents (RMA) are too toxic at the required doses. Therefore, the development of novel RMAs to overcome MDR represents a major challenge to modern cancer chemotherapy. In the present investigation, we describe the effect of oxalyl bis (N-phenyl) hydroxamic acid (OBPHA) and copper N-(2-hydroxy acetophenone) glycinate (CuNG) on multidrug-resistant P-gp-expressing CEM/ADR5000 T-cell acute lymphoblastic leukemia cells. CuNG, a known depleting agent for glutathione (GSH) and inhibitor of glutathione S-transferase (GST) and multidrug resistance-related protein 1 (MRP1), also inhibited P-gp-mediated doxorubicin accumulation and retention. The resistance-modifying effects of OBPHA were stronger than that of CuNG. Both novel RMAs overcame drug resistance more efficiently than verapamil, a well-known P-gp inhibitor. OBPHA and CuNG exposure resulted in an increased doxorubicin accumulation after 1-3h incubation by down-regulation of P-gp expression after 24h incubation. This is a clue that different mechanisms may contribute to modulation of P-gp-mediated drug resistance by these compounds.
...
PMID:Reversal of drug resistance in P-glycoprotein-expressing T-cell acute lymphoblastic CEM leukemia cells by copper N-(2-hydroxy acetophenone) glycinate and oxalyl bis (N-phenyl) hydroxamic acid. 1641 38

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.
...
PMID:Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. 1642 33

Although inorganic arsenicals are toxic and carcinogenic in humans, inorganic arsenite has recently emerged as a highly effective chemotherapeutic agent for acute promyelocytic leukemia (APL). Inorganic arsenicals are enzymatically methylated to monomethylarsonic acid (MMAs(V)), dimethylarsinic acid (DMAs(V)), and trimethylarsine oxide (TMAs(V)O) in mammals. We examined the effects of chronic exposure to methylated arsenicals on arsenic tolerance by using rat normal liver TRL 1215 cells. TRL 1215 cells were exposed for 20 weeks to MMAs(V), DMAs(V), or TMAs(V)O at levels that produced submicromolar cellular concentrations of arsenic. On chronic exposure to these methylated arsenicals, the cells acquired tolerance to acute arsenic cytolethality. Cellular arsenic uptake was reduced in these cells compared to passage-matched control cells. The long-term arsenic exposure increased glutathione S-transferase (GST) activity and cellular glutathione (GSH) levels. Glutathione S-transferase, multidrug resistance-associated proteins (Mrps; efflux transporters encoded by Mrp genes), and P-glycoprotein [P-gp; efflux transporter encoded by multidrug resistance gene (MDR)] had also increased in these cells at the transcript and protein levels. The depletion of cellular GSH and the inhibition of Mrps and P-gp functions increased cellular arsenic uptake and reduced arsenic tolerance in these cells. These results indicate that chronic exposure to methylated arsenicals induces a generalized arsenic tolerance that is caused by increased arsenic excretion. Because accumulation of methylated arsenicals may occur in patients with chronic arsenic poisoning and arsenic-treated APL patients, this study may provide important information regarding chronic arsenic poisoning and the latent risk of developing multidrug resistance in APL therapy using inorganic arsenite.
...
PMID:Chronic exposure to methylated arsenicals stimulates arsenic excretion pathways and induces arsenic tolerance in rat liver cells. 1643 60

Recently, thiolated polymers, so called thiomers, have been reported to modulate drug absorption by inhibition of intestinal P-glycoprotein (P-gp). The aim of the present study was to provide a proof-of-principle for a delivery system based on thiolated chitosan in vivo in rats, using rhodamine-123 (Rho-123) as representative P-gp substrate. In vitro, the permeation enhancing effect of unmodified chitosan, chitosan-4 thiobutylamidine (Ch-TBA) and the combination of Ch-TBA with reduced glutathione (GSH) was evaluated by using freshly excised rat intestinal mucosa mounted in Ussing-type chambers. In comparison to buffer only, Rho-123 transport in presence of 0.5% (w/v) chitosan, 0.5% (w/v) Ch-TBA and the combination of 0.5% (w/v) Ch-TBA/0.5% (w/v) GSH, was 1.8-fold, 2.6-fold, 3.8-fold improved, respectively. Furthermore, enteric-coated tablets based on unmodified chitosan or Ch-TBA/GSH, were investigated in vivo. In rats, the Ch-TBA/GSH tablets increased the area under the plasma concentration time curve (AUC0-12) of Rho-123 by 217% in comparison to buffer control and by 58% in comparison to unmodified chitosan. This in vivo study showed that a delivery system based on thiolated chitosan significantly increased the oral bioavailability of P-gp substrate Rho-123.
...
PMID:In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan. 1661 4

Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron (Fe) release. We have shown that NO-mediated Fe efflux from cells required glutathione (GSH), and we have hypothesized that a GS-Fe-NO complex was released. Hence, we studied the role of the GSH-conjugate transporter multidrug resistance-associated protein 1 (MRP1) in NO-mediated Fe efflux. MCF7-VP cells overexpressing MRP1 exhibited a 3- to 4-fold increase in NO-mediated 59Fe and GSH efflux compared with WT cells (MCF7-WT) over 4 h. Similar results were found for other MRP1-overexpressing cell types but not those expressing another drug efflux pump, P-glycoprotein. NO-mediated 59Fe and GSH efflux were temperature- and energy-dependent and were significantly decreased by the GSH-depleting agent and MRP1 transport inhibitor L-buthionine-[S,R]-sulfoximine. Other MRP1 inhibitors, MK571, probenecid, and difloxacin, significantly inhibited NO-mediated 59Fe release. EPR spectroscopy demonstrated the dinitrosyl-dithiol-Fe complex (DNIC) peak in NO-treated cells was increased by MRP1 inhibitors, indicating inhibited DNIC transport from cells. The extent of DNIC accumulation correlated with the ability of MRP1 inhibitors to prevent NO-mediated 59Fe efflux. MCF7-VP cells were more sensitive than MCF7-WT cells to growth inhibition by effects of NO, which was potentiated by L-buthionine-[S,R]-sulfoximine. These data indicate the importance of GSH in NO-mediated inhibition of proliferation. Collectively, NO stimulates Fe and GSH efflux from cells via MRP1. Active transport of NO by MRP1 overcomes diffusion that is inefficient and nontargeted, which has broad ramifications for understanding NO biology.
...
PMID:Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1. 1667 8

Multidrug resistance (MDR) is a major obstacle to successful application of cancer chemotherapy and also a basic problem in cancer biology. Studies on the molecular basis of MDR have revealed that a number of proteins over express in multidrug resistant cells viz., multidrug resistant MDR1 gene product P-glycoprotein, the multidrug resistance-associated protein (MRP) and enzymes associated with the glutathione (GSH) metabolism. Decreased expression or altered activity of topoisomerase II has also been implicated in MDR. In the present investigation a number of changes in phase II detoxification parameters have been noticed in drug resistant cells but the novel aspect of the present report is the observation that the metal copper is involved in drug resistance. Although copper plays important roles in many human and other biological systems and even in the treatment of cancer but the relation of Cu and drug resistance has not so far been studied in detailed. The present report describes the novel findings that the level of copper increases with the development of drug resistance in Ehrlich ascites carcinoma and in Lewis lung carcinoma cells and also in serum of mice bearing drug resistant cancer cells compared to mice bearing drug sensitive cells; the work indicates the important aspect of treating drug resistant cancer patients by lowering Cu level in the cancerous cells and serum prior to treatment.
...
PMID:The role of copper in development of drug resistance in murine carcinoma. 1678 40

Glutathione (GSH) depletion has been implicated in the pathogenesis of neurological diseases. During GSH depletion, cells of the blood-brain barrier (BBB) are subjected to chronic oxidative stress. In this study, we investigated the effect of such stress, produced with the GSH synthesis inhibitor l-buthionine-(S,R)-sulfoximine (BSO), on expression of P-glycoprotein (Pgp) in primary cultured rat brain microvessel endothelial cells that comprise the blood-brain barrier (BBB). Application of BSO to cell monolayers at concentrations up to 800 microm caused increases in expression of Pgp. Concentrations >or= 400 microm BSO decreased cell viability. Application of 200 microm BSO caused a significant increase in Pgp function activity, as assessed by rhodamine 123 (Rh123) accumulation experiments. At this concentration, BSO produced time-dependent decreases in levels of intracellular GSH and increases in levels of intracellular reactive oxygen species (iROS). The increases were also observed within 48 h following BSO treatment in mdr1a and mdr1b mRNA. Exposure of cells to BSO for 24 h produced maximal effects in the accumulation of iROS, and in expression and function of Pgp. The ROS scavenger N-acetylcysteine prevented ROS generation and attenuated the changes of both expression and activity of Pgp induced by BSO. Therefore, the transport of Pgp substrates may be affected by changing Pgp expression under conditions of chronic oxidative stress induced by GSH depletion.
...
PMID:Up-regulation of P-glycoprotein expression by glutathione depletion-induced oxidative stress in rat brain microvessel endothelial cells. 1692 59

Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics, such as several cytostatic drugs, through conjugation with glutathione (GSH). Pi class GST (GST P) liver expression is associated with preneoplastic and neoplastic development and contributes with the drug-resistance phenotype. Ethacrynic acid (EA) is an inhibitor of rat and human GSTs. In addition, causes lipid peroxidation in isolated rat hepatocytes. Therefore, we decided to evaluate the role of the GST/GSH system in isolated hepatocytes from preneoplastic rat livers (IP) in the presence of EA and determine the cytotoxicity of the drug. Our results showed a resistance to the toxic effects of EA since viability and cellular integrity values were significantly higher than control. Initial levels of thiobarbituric acid reactive substances (TBARS) in IP hepatocytes were significantly higher than control and the presence of EA did not change TBARS levels. A diminution in intracellular total GSH was observed by treating with EA isolated hepatocytes from both groups. However, the initial total GSH levels were higher in IP hepatocytes than in control. Immunoblotting analysis showed the presence of GST P in IP animals only. Although alpha and mu class isoenzymes levels were decreased in IP hepatocytes, total GST activity was 1.5-fold higher than in control. In addition, multidrug-resistance protein 2 (Mrp2) showed fivefold decreased levels in IP hepatocytes. In conclusion, increased total GSH, decreased Mrp2 levels and the presence of GST P could be critical factors involved in the resistance of IP hepatocytes to the toxicity of EA.
...
PMID:Hepatocytes isolated from preneoplastic rat livers are resistant to ethacrynic acid cytotoxicity. 1734 Jan 22

The aim of this work was to determine the functional activities of four different antioxidative enzymes (glutathione reductase, glutathione-S-transferase, glutathione peroxidase, thioredoxin reductase) and the protein expression of three ATP-binding cassette transporters (P-glycoprotein, multidrug resistance protein 1, multidrug resistance protein 2) in a panel of 14 human cancer cell lines. Enzyme activities and transporter expression were then correlated with the in-vitro cytotoxic activities (GI50 values) of 19 standard antitumor drugs. Analogous data from the National Cancer Institute were used for comparison. The GI50 values of the platinum complexes, alkylating agents, antimetabolites, topoisomerase inhibitors and antimitotic drugs were determined by crystal violet or 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay. Standard enzymatic assays employed to measure the glutathione peroxidase, glutathione-S-transferase, glutathione reductase and thioredoxin reductase activities. The protein expression of the ATP-binding cassette transporter proteins was investigated by the Western-blot method. The delta method was used to normalize the data before bivariant correlation analysis. Only a few correlations between enzyme and cytotoxic activities of the antitumor agents were found. The GI50 values for melphalan and camptothecin correlated positively with the activity of glutathione-S-transferase, whereas GI50 values for methotrexate correlated positively with the cellular activities of both glutathione reductase and thioredoxin reductase. A significant correlation between glutathione reductase and thioredoxin reductase activities was found in our panel of cell lines. Neither P-glycoprotein nor multidrug resistance protein 2 expression could be detected by Western blot analysis in any cell lines investigated, but multidrug resistance protein 1 was consistently observed in all but four lines. Multidrug resistance protein 1 expression correlates positively with the GI50 values of several drugs, e.g. vinblastine and etoposide, and negatively with the GI50 values of 5-fluorouracil. The results confirm the complexity of resistance to antitumor agents and show that the GSH-thioredoxin system alone is not a good indication of intrinsic resistance for many of these anticancer drugs.
...
PMID:Correlations between the activities of 19 standard anticancer agents, antioxidative enzyme activities and the expression of ATP-binding cassette transporters: comparison with the National Cancer Institute data. 1735 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---