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)

It has been suggested that expression of the P-glycoprotein transmembrane efflux pump (PGP), encoded by the multi-drug resistance (MDR1) gene, may play a role in the protection of epithelial tissues from a variety of local and systemic toxins. We report that in approximately 50% (6/11) of the population, MDR1 messenger RNA levels in the normal urinary epithelium are comparable to those found in the highest expressing tissues in the body, and suggest a role for PGP in the normal bladder urothelium. MDR1 mRNA levels in the normal urothelium do, however, vary over a 60-fold range between individuals, and furthermore are uniformly significantly lower (about 6-fold, P</=0.01) in all low-grade bladder carcinoma samples. On the basis of these observations we conclude that low MDR1 mRNA levels are a uniformly consistent characteristic of low-grade bladder tumours, and hypothesize that high MDR1 expression plays a role in protection of the normal bladder from carcinogen exposure, and that individuals with low normal bladder MDR1 mRNA levels may consequently be at an increased risk of developing bladder cancer. Furthermore,the low level of MDR1 expression generally found in low grade superficial tumours may predispose them to additional carcinogen exposure and in this way contribute to possible tumour progression. In addition, MDR1 mRNA levels were observed to be elevated in a significant proportion (approximately 25%, 8/30, P = 0.015) of high grade tumours compared to low grade samples, and may therefore represent a marker of bladder tumour progression.
Carcinogenesis 1996 Mar
PMID:High level expression of the multidrug resistance (MDR1) gene in the normal bladder urothelium: a potential involvement in protection against carcinogens? 863 Nov 51

Expression of P-glycoprotein (P-gp), the mdr gene product, was investigated in primary cultures of rat and human hepatocytes exposed to 2-acetylaminofluorene (2-AAF). Increased levels of mdr1 mRNAs were evident in 2-AAF-treated rat hepatocytes by Northern blot analysis using rat mdr gene-specific probes, while transcripts of the mdr2 and mdr3 genes were decreased and unaffected respectively. Rat hepatocytes exposed to 2-AAF were also found to accumulate doxorubicin, an anticancer drug known to be transported by P-gp, poorly, thereby demonstrating that 2-AAF-mediated mdr1 induction resulted in increased P-gp activity. In contrast to their rat counterparts, human hepatocytes obtained from 10 individuals exhibited no change in both MDR1 and MDR2 mRNA levels, as well as in doxorubicin intracellular retention, in response to 2-AAF treatment, while cytochromes P-450 CYP1A1 and CYP1A2 were induced in both human and rat hepatocyte cultures. These data provide strong evidence that regulation of expression of mdr genes in liver cells in response to carcinogens such as 2-AAF is gene- and species-specific.
Carcinogenesis 1996 May
PMID:Differential regulation of mdr genes in response to 2-acetylaminofluorene treatment in cultured rat and human hepatocytes. 864 Sep 28

Protein kinase C (PKC) is an enzyme family with serine/threonine kinase function which is involved in the transduction of signals for cell proliferation and differentiation. The important role played in processes relevant to neoplastic transformation, carcinogenesis and tumor cell invasion renders PKC a potentially suitable target for anticancer therapy. Bryostatin 1, a macrocyclic lactone isolated from Bugula nerutina, is a partial PKC agonist, and has shown potent antineoplastic properties in vitro and in vivo. Staurosporine, an alkaloid isolated from microbial sources, is ine of the most potent PKC inhibitors and has shown high antiproliferative activity in vitro, but poor selectivity. Staurosporine analogs have thus been synthesize with the aim of obtaining more selective PKC inhibition; among these, CGP 41251 has shown reduced PKC inhibitory activity, but a higher degree of selectivity when assayed for inhibition of different kinases. Several studies indicate a role for PKC in the regulation of the multidrug resistance (MDR) phenotype, since several PKC inhibitors are able to partially reverse MDR and inhibit P-glycoprotein (Pgp) phosphorylation. The MDR phenotype is also associated with variation in PKC isoenzyme content, in particular with PKC-alpha overexpression. While adequate PKC modulation might offer an attractive concept to modulate MDR, other potential mechanisms of PKC interaction with anticancer drugs exist and have been documented, such as the enhancement of chemotherapy-induced apoptosis by safingol, a specific PKC inhibitor. Three phase I clinical trials with bryostatin have been completed so far and have shown that myalgia is the dose-limiting toxicity, while some antitumor activity is evident. Safingol is presently undergoing a phase I clinical trial in combination with doxorubicin. While no definitive data are presently available, it appears that safingol plasma levels approach those associated with chemopotentiation in animals and no pharmacokinetic interaction between the two drugs exists. Drugs targeting PKC are well work considering for clinical trials, particularly for their potential as modulators of currently available cytotoxic agents.
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PMID:Protein kinase C: a worthwhile target for anticancer drugs? 914 7

The multidrug resistance (mdr) genes encode P-glycoproteins, integral membrane proteins which function as drug efflux transporters. Exposure of animals in vivo and cells in vitro to a variety of xenobiotics leads to increased mdr1 gene expression and higher levels of P-glycoprotein. This response may protect cells from the cytotoxic effects of these compounds. In this investigation we functionally expressed the rat mdr1b gene in NIH 3T3 cells and assessed the ability of the encoded P-glycoprotein to protect these cells from the cytotoxicity of xenobiotics known to induce mdr1b expression. In long-term colony survival assays, stably expressed mdr1b conferred resistance to cytotoxic drugs such as colchicine, vinblastine and doxorubicin, but not to 5-fluorouracil nor to the carcinogens aflatoxin B1 and N-hydroxy-acetylaminofluorene. The mdr reversal agent verapamil restored cytotoxicity of colchicine, doxorubicin, actinomycin D, vinblastine and taxol, but had no effect on the sensitivity of these cells to 5-fluorouracil, aflatoxin B1 or N-hydroxy-acetylaminofluorene. In a competitive transport assay, verapamil and, to a lesser extent, colchicine blocked the increased efflux of the fluorescent dye rhodamine 123 from mdr1b-transfected cells, whereas aflatoxin B1 did not compete for this export. These data demonstrate that expression of the rat mdr1b encoded P-glycoprotein can protect cells from a diverse group of compounds previously identified to be mdr substrates, however, other effective inducers of mdr expression, such as aflatoxin B1 and N-hydroxy-acetylaminofluorene, remain potent cytotoxins despite high levels of P-glycoprotein. The fact that compounds which are not themselves substrates can induce P-glycoprotein expression may have implications for pharmacokinetic interactions and chemotherapy.
Carcinogenesis 1997 Nov
PMID:Functional characterization of the rat mdr1b encoded P-glycoprotein: not all inducing agents are substrates. 939 29

Epidemiologic studies have stated the progressive increase of bladder tumors during the last decades. The aim of our review is to refer to factors implicated in bladder carcinogenesis (such as activated oncogenes, growth factors and chromosomal aberrations) and to resistance to drug uptake (i.e., multidrug resistance gene and P-glycoprotein). The review also provides information of diagnostic and prognostic significance, based on DNA analysis of transitional cancer cells. In addition to cytometric data, alternative counterings for estimation of the S-phase fraction, useful in indicating the biologic behavior of bladder cancer, are presented. Knowledge of such mechanisms results in a better approach to the diagnosis, prognosis and prevention of bladder carcinomas, especially those that do not respond to systemic intravesical chemotherapy. We have tried to mention all significant factors related to the development of bladder cancer. We conclude that the progress made in understanding the pathogenesis of bladder cancer has been significant. However, more studies are needed in order to introduce and adopt reliable criteria to accurately predict the clinical behavior.
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PMID:Recent aspects in the diagnosis and prognosis of bladder cancer. 967 11

P-glycoproteins encoded by multidrug resistance type 1 (mdr1) genes mediate ATP-dependent efflux of numerous lipophilic xenobiotics, including several anticancer drugs, from cells. Overexpression of mdr1-type transporters in tumour cells contributes to a multidrug resistance phenotype. Several factors shown to induce mdr1 overexpression (UV irradiation, epidermal growth factor, tumour necrosis factor alpha, doxorubicin) have been associated with the generation of reactive oxygen species (ROS). In the present study, primary rat hepatocyte cultures that exhibit time-dependent overexpression of the mdr1b gene were used as a model system to investigate whether ROS might participate in the regulation of intrinsic mdr1b overexpression. Addition of H2O2 to the culture medium resulted in a significant increase in mdrlb mRNA and P-glycoprotein after 3 days of culture, with maximal (approximately 2-fold) induction being observed with 0.5-1 mM H2O2. Furthermore, H2O2 led to activation of poly(ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, indicating that ROS reached the nuclear compartment. Thus, extracellularly applied H2O2 elicited intracellular effects. Treatment of rat hepatocytes with the catalase inhibitor 3-amino-1,2,4-triazole (2-4 mM for 72 h or 10 mM for 1 h following the hepatocyte attachment period) also led to an up-regulation of mdrlb mRNA and P-glycoprotein expression. Conversely, antioxidants (1 mM ascorbate, 10 mM mannitol, 2% dimethyl sulphoxide, 10 mM N-acetylcysteine) markedly suppressed intrinsic mdr1b mRNA and P-glycoprotein overexpression. Intracellular steady-state levels of the mdrl substrate rhodamine 123, determined as parameter of mdr1-type transport activity, indicated that mdr1-dependent efflux was increased in hepatocytes pretreated with H2O2 or aminotriazole and decreased in antioxidant-treated cells. The induction of mdr1b mRNA and of functionally active mdr1-type P-glycoproteins by elevation in intracellular ROS levels and the repression of intrinsic mdrlb mRNA and P-glycoprotein overexpression by antioxidant compounds support the conclusion that the expression of the mdr1b P-glycoprotein is regulated in a redox-sensitive manner.
Carcinogenesis 1999 Mar
PMID:Reactive oxygen species participate in mdr1b mRNA and P-glycoprotein overexpression in primary rat hepatocyte cultures. 1019 May 54

Cooked-food mutagens formed when frying meat have been suggested to contribute to the etiology of colon, breast and prostate cancer. The most prevalent of these mutagens is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which after absorption is bioactivated by both phase I and phase II enzymes. Although available data suggest absorption of PhIP in humans, the extent and mechanism of absorption are unknown. In the present study we examined the transport of [(3)H]PhIP through the human Caco-2 intestinal epithelial cell monolayer, a well-accepted model of human intestinal absorption. The influx, or absorption, was extensive and linear for 2 h and up to a PhIP concentration of 5 microM. Still, the basolateral to apical efflux [apparent permeability coefficient (P(app)) 54.2 +/- 0.7x10(-6) cm/s, mean +/- SEM, n = 24] was 3.6 times greater than the apical to basolateral influx (P(app) 15.1 +/- 0.6x10(-6) cm/s, n = 21, P < 0.0001). Equilibrium exchange experiments demonstrated the efflux to be a true active process. Preincubations with verapamil, an inhibitor of P-glycoprotein-mediated transport, or MK-571, an inhibitor of multidrug resistance-associated protein-mediated transport, stimulated influx and reduced efflux of PhIP, suggesting that PhIP is a substrate for both of these transporters. These findings should be considered when determining exposure to the cooked food mutagens.
Carcinogenesis 1999 Nov
PMID:Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps. 1054 19

Prostate cancers are resistant to many anticancer agents at the time of presentation. P-glycoprotein (P-gp) is believed to mediate multidrug resistance phenotype. To elucidate the possible role of P-gp in such an intrinsic drug resistance of prostate cancers, its expression was examined immunohisochemically using two P-gp isoform-specific monoclonal antibodies (mAbs) with the paraffin embedded prostate samples derived from five nonmalignant and 30 untreated prostate cancer patients. In all of five normal prostate tissues, P-gp was consistently detected with both mAbs in the epithelial cells, especially at their apical site, and the level of expression was higher in the inner zone than in outer zone. On the other hand, tumor cells expressed P-gp heterogeneously in distribution and intensity; in 25 of 30 malignant cases P-gp expression was clearly demonstrated, whereas its expression was only faintly detected in other cases. However, the staining intensities for P-gp in prostate cancer cells were generally lower than in normal prostate epithelial cells. Thus, not only normal prostate epithelial cells but prostate cancer cells express at least MDR1 P-gp isoform. These results suggest that P-gp expression might play some role in intrinsic drug resistance of prostate cancer cells to many cytotoxic drugs as well as in relative resistance of the inner zone cells to the prostate carcinogenesis.
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PMID:Demonstration of MDR1 P-glycoprotein isoform expression in benign and malignant human prostate cells by isoform-specific monoclonal antibodies. 1070 36

Transport across hepatocyte plasma membranes is a key parameter in hepatic clearance and usually occurs through different carrier-mediated systems. Sinusoidal uptake of compounds is thus mediated by distinct transporters, such as Na(+)-dependent or Na(+)-independent anionic transporters and by some cationic transporters. Similarly, several membrane proteins located at the apical pole of hepatocytes have been incriminated in the excretion of compounds into the bile. Indeed, biliary elimination of anionic compounds, including glutathione S-conjugates, is mediated by MRP2, whereas bile salts are excreted by a bile salt export pump (BSEP) and Class I-P-glycoprotein (P-gp) is involved in the secretion of amphiphilic cationic drugs, whereas class II-P-gp is a phospholipid transporter. The expression of hepatic transporters and their activity are regulated in various situations, such as ontogenesis, carcinogenesis, cholestasis, cellular stress and after treatment by hormones and xenobiotics. Moreover, a direct correlation between a defect and the absence of transporter with hepatic disease has been demonstrated for BSEP, MDR3-P-gp and MRP2.
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PMID:Expression and regulation of hepatic drug and bile acid transporters. 1109 Sep 58

Cells have some inborn resistance to harmful factors, which could be called physiological or natural resistance. The mechanisms of multixenobiotic resistance (MXR) and multidrug resistance (MDR) have common features in the formation of acquired resistance in microorganisms, carcinogenesis, tumour metastases and chemotherapy or irradiation. ATP-dependent membrane P-glycoprotein, as an MDR efflux pump, glutathione S-transferases and other products of evolutionary resistance-related genes arised for exportation and detoxification of cytotoxic xenobiotics and drugs are transmitted from bacteria to man. On the one hand, this evolutionary MXR as a common biological defence mechanism is a "driving" power to conserve homeostasis of cells, tissues and organs. On the other hand, mutation, selection and simplification of properties are the causes of functional and morphological changes in tumour cells which regress to a more primitive mode of existence (atavism) for adaptation to survival. In the present work are presented data on the forms of E. coli resistant to antibiotics and of sarcoma 45 resistant to alkylic preparations. They may be helpful in revealing the causes of resistance and acquired accelerated growth of cells. The development of tumours as fibromas 14-15 years following injection of a vital dye trypan blue into human skin supports our conception that neoplastic growth is a particular case of the evolutionary resistance of cells adapted to the damaging factors. So, tumour cells adopting the enhancement mechanisms of general biological persistent resistance, i. e. undergoing repeated cycles of malignancy enhancement, adapt themselves to survive under the changed unfavourable conditions.
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PMID:Evolutionary malignant resistance of cells to damaging factors as common biological defence mechanism in neoplastic development. Review of conception. 1114 27


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