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)

Microvessel density was investigated by immunostaining endothelial cells for factor VIII antigen in 84 non-small cell lung carcinomas and compared with the expression of several resistance-related proteins. Glutathione S-transferase-pi, thymidylate synthase, metallothionein and, with limitations, P-glycoprotein were overexpressed in tumors with poor vascularization.
Carcinogenesis 1995 Sep
PMID:Up-regulation of resistance-related proteins in human lung tumors with poor vascularization. 755 65

The overexpression of P-glycoprotein (Pgp) appears to be responsible for multidrug resistance in some human cancers. The molecular basis of this overexpression is not understood. We have used primary monolayer cultures of adult rat hepatocytes as a model system to study the regulation of Pgp gene expression (Lee et al., J. Cell. Physiol., 157: 392-402, 1993). We observed a dramatic and specific overexpression of class II Pgp as a function of the time in culture. This isoform of Pgp, which is expressed at a very low level in normal liver, has also been shown to be predominantly overexpressed in several models of rat liver carcinogenesis. In the present study, we have used nuclear run-on assays and mRNA decay studies to investigate the mechanism for the overexpression of class II Pgp in cultured hepatocytes. We conclude that an increased mRNA stability is the major factor involved in the increased expression of class II Pgp. Studies using various drugs indicate that the integrity of the cytoskeleton is important for the maintenance of high expression of class II Pgp. Disruption of the cytoskeleton in cultured hepatocytes with cytochalasin D did not affect the transcriptional activity of the class II Pgp gene but rapidly destabilized its mRNA. This raises the possibility that an association between class II Pgp mRNA and cytoskeletal elements may underlie the mechanism that regulates class II Pgp mRNA stability. These findings have important implications for our understanding of the overexpression of class II Pgp during liver carcinogenesis.
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PMID:Overexpression of the class II P-glycoprotein gene in primary rat hepatocyte culture: evidence for increased mRNA stability. 779 2

We used a series of P-glycoprotein (P-gp) expressing multidrug-resistant (MDR) cells, developed from human breast cancer MCF-7 cells by exposure to Adriamycin, to investigate the effects of flavonoids on P-gp-mediated efflux mechanisms for chemical carcinogens. We previously showed that MDR cells derived from exposure to Adriamycin are cross-resistant to a chemical carcinogen, benzo(a)pyrene, due to its cellular efflux by the P-gp-mediated putative drug efflux pump. Our current studies extended this observation to another polycyclic aromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene, known to induce mammary tumors in animals. In our attempt to find naturally occurring dietary compounds which may stimulate the P-gp-mediated efflux of carcinogens, we found that certain flavonols, kaempferol, quercetin, and galangin, are potent stimulators of the P-gp-mediated efflux of 7,12-dimethylbenz(a)-anthracene. The increased efflux decreased the cellular burden of 7,12-dimethylbenz(a)anthracene. Since these flavonol compounds are widely distributed in fruits and vegetables, their stimulatory effect on P-gp may be a mechanism relevant to carcinogenesis and the observed lowered cancer risk in humans with higher dietary intake of fruits and vegetables.
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PMID:Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells. 790 98

Spontaneous and culture condition-dependent changes in P-glycoprotein expression and activity have been monitored in primary cultures of rat hepatocytes by using immunoblotting, PCR and fluorimetric techniques. In hepatocytes cultured in basal medium without addition of dexamethasone or 3-methylcholanthrene, mdr mRNA and P-glycoprotein increased progressively throughout a 72 h culture period, in concert with an enhancement in the ability to extrude the fluorescent dye Rhodamine-123. Addition of 1 microM dexamethasone to the culture medium slowed down the increase in mdr mRNA and P-glycoprotein, while inducing a significant increase in the efficiency of R-123 efflux. Addition of either 100 nM or 10 microM DEX produced different changes in mdr mRNA and protein, unrelated to the rate of Rhodamine-123 extrusion. When 50 microM 3-methylcholanthrene was added to the culture medium in the absence of any hormone supplementation, no significant changes in P-glycoprotein activity and expression took place, in comparison with control cultures. On the contrary, in the presence of dexamethasone (100 nM and 1 microM), 3-methylcholanthrene induced an increase in mdr mRNA and in the amount of immunoblottable protein during culture, without producing any concomitant increase in the efficiency to extrude Rhodamine-123. The last phenomenon resulted to be an artefact, since 3-methylcholanthrene was shown to inhibit Rhodamine-123 transport competitively. These results indicate that rat hepatocyte P-glycoprotein may be variously modulated in vitro, by supplementing culture medium with hormones and/or xenobiotics. Functional activity of the P-glycoprotein is not necessarily related with protein amount and/or mdr RNA.
Carcinogenesis 1994 Feb
PMID:Differential modulation of P-glycoprotein expression by dexamethasone and 3-methylcholanthrene in rat hepatocyte primary cultures. 790 6

Using indirect immunofluorescence with fluorescein isothiocyanate-conjugated antibodies, in combination with flow cytometry (FCM), we have developed a technique to detect the alpha, mu and pi isozymes of GST in cell suspensions from normal rat liver, and in H4IIE cells, a rat hepatoma cell line. Cell suspensions fixed in 1% paraformaldehyde were observed to require cell membrane permeation with lysolecithin to allow access and binding of antibodies to immunoreactive proteins within the cytoplasm. FCM analysis indicated normal rat hepatocytes to be positive for GST alpha and mu, but not GST pi, and the H4IIE cells to be positive for all three GST isozymes. Further analysis by FCM for the expression of P-glycoprotein (mdr), a membrane-associated protein product of the multidrug resistance gene, showed an association between the presence of GST pi and mdr in the two cell types. Thus, mdr was detected in significant amounts in H4IIE cells, but not in rat hepatocytes. The method described here has potential applications in screening, sorting and further characterisation for GST pi-positive hepatocytes for mechanistic studies during sequential rat liver carcinogenesis, as well as for characterisation of human tumors for the expression of different GST isozymes and P-glycoprotein during therapeutic management.
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PMID:Glutathione S-transferases and P-glycoprotein in normal rat hepatocytes and hepatoma cells: analysis using flow cytometry. 791 42

P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been widely studied. Recent investigations have begun to focus on the relationship between Pgp detection in tumors and treatment outcome. In several types of tumors, detection of Pgp correlates with poor response to chemotherapy and shorter survival. P-glycoprotein over-expression often occurs upon relapse from chemotherapy but may also occur at the time of diagnosis. Studies of experimental rat liver carcinogenesis have shown that Pgp expression increases in late stages of carcinogenesis, suggesting that Pgp may be involved in tumor progression. While some of the Pgp isoforms are known to transport hydrophobic chemotherapeutic drugs out of tumor cells, the biologic effects of Pgp overexpression in tumor cells are not fully understood, because the spectrum of substrates for Pgp-mediated transport has not been determined. In the rat liver carcinoma model, strong expression of Pgp is associated with a highly vascular stroma, suggesting that Pgp in tumor cells may affect the connective tissue stroma. The regulation of Pgp appears to be complex, and little is known about how it is up-regulated during carcinogenesis. Further studies of the role of Pgp in malignancy may contribute to our understanding of molecular mechanisms which underlie tumor progression.
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PMID:P-glycoprotein, multidrug resistance and tumor progression. 792 52

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.
Carcinogenesis 1994 Nov
PMID:Metabolic activation of 2-acetylaminofluorene is required for induction of multidrug resistance gene expression in rat liver cells. 795 3

The mouse mdr2 gene (and its human homologue MDR3, also called MDR2) encodes a P-glycoprotein that is present in high concentration in the bile canalicular membrane of hepatocytes. The 129/OlaHsd mice with a homozygous disruption of the mdr2 gene (-/- mice) lack this P-glycoprotein in the canalicular membrane. These mice are unable to secrete phospholipids into bile, showing an essential role for the mdr2 P-glycoprotein in the transport of phosphatidylcholine across the canalicular membrane. The complete absence of phospholipids from bile leads to a hepatic disease, which becomes manifest shortly after birth and shows progression to an end stage in the course of 3 months. The liver pathology is that of a nonsuppurative inflammatory cholangitis with portal inflammation and ductular proliferation, consistent with toxic injury of the biliary system from bile salts unaccompanied by phospholipids. Thus, the mdr2 (-/-) mice can serve as an animal model for studying mechanisms and potential interventions in nonsuppurative inflammatory cholangitis (in a generic sense) in human disease, be it congenital or acquired. When the mice are 4 to 6 months of age, preneoplastic lesions develop in the liver, progressing to metastatic liver cancer in the terminal phase. The mdr2 (-/-) mice therefore also provide a tumor progression model of value for the study of hepatic carcinogenesis. Interestingly, also in this regard, the model mimicks human disease, because chronic inflammation of the biliary system in humans may similarly carry increased cancer risk.
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PMID:Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. 797 54

Previous controversy has risen from the purported equivalence of the volume-sensitive chloride channels with P-glycoprotein. The aim of this study was to investigate the association between expression of volume-sensitive Cl- channels and the process of malignant transformation of cervical epithelial cells. We studied the activations of volume-sensitive and cAMP-mediated chloride currents in various human cervical squamous cells that were representative of different stages of cervical carcinogenesis, i.e., normal cervical epithelium, low-grade cervical intraepithelial neoplasia, carcinoma in situ, and invasive carcinoma using the whole-cell patch clamp technique. The volume-sensitive chloride channels, however, were significantly activated only in the four cervical cancer cell lines, primary culture cells of carcinoma in situ, and invasive cancer of the cervix. The expression of volume-sensitive chloride currents was independent of the state of human papillomavirus positivity. When these cells were exposed to hypotonic shock, the cells swelled, and outward rectified chloride currents were observed. These effects were readily reversed by returning the cells to isotonic medium. In addition, 4,4'-diisothiocyanatostilbene-2,2-disulfonic acid, 1,9-dideoxyforskolin, and verapamil reversibly abolished the volume-sensitive Cl- currents. In contrast, none of the cells from normal cervices and human papillomavirus-immortalized cell lines, the in vitro equivalent of low-grade cervical intraepithelial neoplasia, developed substantial chloride currents on exposure to hypotonicity. cAMP-mediated chloride currents were ubiquitously activated in all cervical squamous cells, regardless of the stages of carcinogenesis. This is the first report suggesting an in vivo association between the development of volume-sensitive chloride currents and human carcinogenesis.
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PMID:Volume-sensitive chloride channels associated with human cervical carcinogenesis. 852 96

Recently, many potent inhibitors of protein serine/threonine phosphatases (PPs) have been found. Some of them have proven to be tumor promoters in mouse skin two-step carcinogenesis and rat liver medium-term tests. Among these inhibitors, okadaic acid (OA) selectively inhibits PP2A, and its use has therefore been proposed to facilitate analysis of biological roles of this phosphatase. OA shows bimodal effects on in vitro transformation and, in addition to such epigenetic changes, also induces marked genetic changes. OA treatment for more than 1 week flattened NIH 3T3 transformants irreversibly, with loss of the transfected genes. It is also known to induce diphtheria toxin-resistant mutations in Chinese hamster lung cells and sister chromatid exchanges (SCEs) in Chinese hamster ovary cells and human lymphocytes. To analyze roles of protein phosphatases in gene stability, we isolated OA-resistant mutants. They were proven to have a mutation in the PP2A alpha catalytic subunit, in which cysteine 269 had been substituted for glycine; and it was demonstrated that this region interacts with OA. The recombinant mutant protein was 4 approximately 9-fold more resistant to OA than the wild type. Although the OA resistant mutants of CHO cells expressed high levels of P-glycoprotein, inhibition of PP2A itself was suggested to lead to SCE induction. However, the number of molecular species of PP which are known to be sensitive to OA continues to increase, and we have isolated cDNA for a novel type of OA sensitive PP. Our studies indicate that the fact that the roles of PP2A cannot be elucidated using only OA is of crucial importance.
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PMID:Protein serine/threonine phosphatases as binding proteins for okadaic acid. 853 25


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