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)

We studied transepithelial transport of 3H-labeled hydrophobic cationic drugs in epithelia formed by wild-type and by drug-resistant Madin-Darby canine kidney (MDCk) cells that had been infected with a retrovirus carrying the multidrug-resistance (MDR1) cDNA which encodes the P-glycoprotein. P-glycoprotein is an ATP consuming plasma membrane multidrug transporter responsible for the efflux of cytotoxic chemotherapeutic drugs from resistant cancer cells. Wild-type MDCK cells have small amounts of P-glycoprotein detected by immunoprecipitation. Net transepithelial transport across wild-type MDCK epithelia was demonstrated. Basal to apical flux of 100 nM vinblastine was about six times higher than apical to basal flux. Addition of unlabeled vinblastine reduced basal to apical flux of tracer and increased apical to basal flux of tracer, a pattern expected if there is a saturable pump that extrudes vinblastine at the apical plasma membrane. Daunomycin, vincristine, and actinomycin D were also actively transported and at 20 microM these agents inhibited transport of vinblastine, suggesting that wild-type MDCK cells have a common transporter for all these drugs. Vinblastine transport was also inhibited by 20 microM verapamil, which inhibits the multidrug transporter and reverses multidrug-resistance in non-polarized cells. Net transepithelial transport of all these cytotoxic drugs and of verapamil was much higher in epithelia formed by MDCK cells infected with a human MDR1 virus (MDR-MDCK) which is expressed on the apical surface of MDR-MDCK monolayers. Because the transport of these cytotoxic drugs and verapamil is increased in MDR-MDCK epithelia compared to wild-type MDCK epithelia, transport in both these cell populations can be attributed to P-glycoprotein. These results are consistent with a role for P-glycoprotein in multidrug secretory transport across the epithelium of the proximal tubule since P-glycoprotein is normally expressed on the apical membrane of proximal tubule cells.
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PMID:Transepithelial transport of drugs by the multidrug transporter in cultured Madin-Darby canine kidney cell epithelia. 257 70

The human MDR (P-glycoprotein) gene family is known to include two members, MDR1 and MDR2. The product of the MDR1 gene, which is responsible for resistance to different cytotoxic drugs (multidrug resistance), appears to serve as an energy-dependent efflux pump for various lipophilic compounds. The function of the MDR2 gene remains unknown. We have examined the structure of the human MDR gene family by Southern hybridization of DNA from different multidrug-resistant cell lines with subfragments of MDR1 cDNA and by cloning and sequencing of genomic fragments. We have found no evidence for any other cross-hybridizing MDR genes. The sequence of two exons of the MDR2 gene was determined from genomic clones. Hybridization with single-exon probes showed that the human MDR1 gene is closely related to two genes in mouse and hamster DNA, whereas MDR2 corresponds to one rodent gene. The human MDR locus was mapped by field-inversion gel electrophoresis, and both MDR genes were found to be linked within 330 kilobases. The expression patterns of the human MDR genes were examined by enzymatic amplification of cDNA. In multidrug-resistant cell lines, increased expression of MDR1 mRNA was paralleled by a smaller increase in the levels of MDR2 mRNA. In normal human tissues, MDR2 was coexpressed with MDR1 in the liver, kidney, adrenal gland, and spleen. MDR1 expression was also detected in colon, lung, stomach, esophagus, muscle, breast, and bladder.
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PMID:Structure and expression of the human MDR (P-glycoprotein) gene family. 257 Oct 78

The fact that cancer cell acquires multidrug resistance to carcinostatics at cancer treatment is a very important subject clinically. The mode of multidrug-resistance is complicated, but the gene associated with multidrug resistance (MDR 1) has been isolated. It has become evident that MDR 1 gene carries membrane glycoprotein (P-glycoprotein) which occurs in the cell acquired drug-resistance. Assessment has been made this time regarding the occurrence of P-glycoprotein in the tumorous cells and tissues by the use of monoclonal antibody (C 219) to P-glycoprotein. Occurrence of P-glycoprotein in malignant lymphoma exhibited positivity in 9 cases out of 36 immunohistologically. 170 KD P-glycoprotein was detected in 4 cases out of 10 at Western blotting analysis of the protein isolated from the nuclear cell in the peripheral blood in the patients with leukemia. Further, P-glycoprotein positive cases were all progressive cases clinically and showed resistance to treatment. From these results, it has been clarified that occurrence of P-glycoprotein in haematological tumors is related to multidrug resistance.
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PMID:[Expression of P-glycoprotein (multidrug-resistance gene product) in haematological tumors]. 257 82

Sixteen human breast carcinomas were subjected to molecular biological and biochemical analyses to determine tumor cell MDR-1 (P-glycoprotein) levels and progesterone receptor content. The results of these analyses disclosed a strong reciprocal and inverse correlation between levels of tumor cell-specific MDR-1 complementary hybrids and progesterone receptor content. These results suggest that the mechanisms which control expression of the P-glycoprotein gene and the progesterone receptor are interrelated and antagonistic, a result with obvious molecular biological, physiological, and clinical implications.
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PMID:Human breast carcinoma cell levels of MDR-1 (P-glycoprotein) transcripts correlate in vivo inversely and reciprocally with tumor progesterone receptor content. 257 82

Intrinsic and acquired multidrug resistance is an important problem in cancer therapy. Multidrug resistance results from overexpression of the MDR 1 gene, which encodes a drug-efflux pump called P-glycoprotein. We have isolated a 1-kilobase genomic fragment containing the major transcription initiation sites for the human MDR 1 gene. Ribonuclease protection experiments using this fragment indicate that normal human adrenal, colon, and liver cells, the human hepatoma cell line HepG2, and vinblastine-selected human KB multidrug-resistant cells initiate transcription of the MDR 1 gene at the same site within this fragment. The 0.43-kilobase region upstream from the major transcription initiation site linked to the chloramphenicol acetyltransferase gene showed promoter activity in CV-1 monkey kidney cells and in human KB cells. The putative promoter region has a consensus CAAT box and two GC box-like sequences, but no TATA sequence. This identification and isolation of promoter sequences for the MDR 1 gene will permit studies on how expression of this gene is regulated in normal human tissues and cancers.
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PMID:Isolation and sequence of the promoter region of the human multidrug-resistance (P-glycoprotein) gene. 289 92

Multidrug resistant cells are characterized by decreased drug accumulation and retention, thought to be mediated by a high molecular weight glycoprotein, P-glycoprotein (P-gp). Agents such as verapamil have been shown to increase anticancer drug cytotoxicity and increase the amount of drug accumulated and retained by such cells. We show here that in addition to verapamil, reserpine, chloroquine, quinine, quinacrine, yohimbine, vindoline, and catharanthine also enhance the cytotoxicity of vinblastine (VLB) in a multidrug resistant, human leukemic cell line, CEM/VLB1K, described here for the first time. These cells express P-gp as a doublet that is photoaffinity labeled by the analog of VLB, N(p-azido-[3-125I]salicyl)-N'-beta-aminoethylvindesine ([125I]NASV). Both reserpine and, to a lesser extent, verapamil, compete with [125I]NASV for binding to P-gp. We also found that chloroquine, quinacrine, vindoline, and catharanthine, each of which enhanced VLB cytotoxicity in CEM/VLB1K cells by 10- to 15-fold, similarly inhibited [125I]NASV labeling of P-gp. However, neither quinine nor yohimbine inhibited this labeling, and the inhibition produced by catharanthine and vindoline was the greatest or exclusively on the lower band of the P-gp doublet. Our results suggest a complex relationship between the ability of a compound to modulate MDR and its ability to compete for binding to P-gp.
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PMID:Effects of indole alkaloids on multidrug resistance and labeling of P-glycoprotein by a photoaffinity analog of vinblastine. 289 41

We have examined the relationship between transformation and multidrug resistance by employing the v-H-ras or v-raf oncogenes to transform rat liver epithelial (RLE) cells in vitro. The data indicate that transformation of RLE cells with v-H-ras or v-raf results in increased resistance to the cytotoxins adriamycin, vinblastine and 2-acetylaminofluorene. This multidrug resistance is accompanied by increasing expression of P-glycoprotein (MDR-1) and glutathione-S-transferase P (GST-P). Thus, neoplastic transformation of RLE cells with v-raf or v-H-ras, independently of chemical exposure, results in multidrug resistance.
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PMID:Transformation of rat liver epithelial cells with v-H-ras or v-raf causes expression of MDR-1, glutathione-S-transferase-P and increased resistance to cytotoxic chemicals. 290 2

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. We have studied here the recently identified transport-associated proteins, MRP and LRP, and the well-known drug resistance marker P-glycoprotein using a panel of 16 human melanoma cell lines and 71 benign and malignant melanocytic tissue samples. By flow cytometry and immunohistochemistry, expression of P-glycoprotein was not detectable on the protein level in the 10 cell lines analyzed, although by reverse transcriptase polymerase chain reaction, MDR-1 gene expression was demonstrated in 2 of 10 cell lines. In addition, immunohistology revealed P-glycoprotein expression in only 1 of 71 melanocytic lesions. In contrast, MRP was detected in a subset of melanoma cell lines by reverse transcriptase polymerase chain reaction and immunohistology (4 of 10). LRP expression was observed in 8 of 10 melanoma cell lines by immunochemistry and in 10 of 10 by reverse transcriptase polymerase chain reaction. Furthermore, MRP was detected immunohistologically in almost 50% of primary and metastatic melanoma specimens, although no significant differences were found between metastases taken before or after chemotherapy. Expression of LRP was detected in a subset of nevi with nevus cells exhibiting up to 25% positive LRP reactivity. In 13 of 21 primary melanomas and 23 of 37 metastases, more than 25% of tumor cells were stained by the LRP-56 monoclonal antibody. Particularly in the group of metastases with more than 50% of LRP-positive cells, 7 of 11 of the metastases had been previously exposed to chemotherapeutic drugs. Although the expression of membrane transport proteins may explain only the chemoresistance toward lipophilic, natural compounds and not resistance against alkylating agents, the lack of P-glycoprotein expression after chemotherapeutic treatment and the significant expression of MRP and LRP in melanoma cells provide first insights into the drug-resistant phenotype in melanoma. Additional studies analyzing the role of MRP and LRP in chemoresistance of melanoma are warranted.
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PMID:Membrane transport proteins associated with drug resistance expressed in human melanoma. 749 78

We isolated revertant and resistant clones from multidrug-resistant K562/ADM cells and evaluated the expression of P-glycoprotein and the DNA copy number of MDR1. The 9 revertant clones contained 2- to 26-fold DNA copies of MDR1; however, they expressed an extensively decreased P-glycoprotein compared with K562/ADM, while the 10 multidrug-resistant clones contained 4- to 48-fold DNA copies, and the expression level of P-glycoprotein was dependent on the copy number of MDR1 DNA. The decreased expression of P-glycoprotein in the revertants was not due only to the loss of the copy number of MDR1 DNA. To elucidate the mechanism of P-glycoprotein expression decrease in the revertants, a revertant clone (R1-5) was fused with a multidrug-resistant clone (A2-1) or with a drug-sensitive clone isolated from K562. Compared with K562 clone, the A2-1 contained 32-fold MDR1 DNA copies and showed 131-fold resistance to Adriamycin. The revertant clone R1-5 contained 26-fold MDR1 DNA copies but expressed only 5% the P-glycoprotein of A2-1 cells and showed only 2-fold resistance to Adriamycin. For selection of intraspecific hybrids, a neomycin-resistant or a blasticidin S-resistant gene was introduced into clones by electroporation of pSV2neo or pSV2bsr. The introduction of these resistant genes did not alter the copy number or expression of MDR1 in the clones. Hybrid cells between R1-5bsr and A2-1neo were found to express 136 +/- 15% of the P-glycoprotein of A2-1 cells evaluated by quantitive flow cytometry. These hybrid cells contained 41- to 48-fold MDR1 copies and showed the multidrug-resistant phenotype, such as decrease of rhodamine123 accumulation and 120- to 210-fold resistance to Adriamycin (compared with K562), indicating that the 'silent' MDR1 genes in the revertant clone R1-5 were activated by cell fusion with an MDR clone. R1-5bsr x K562neo hybrids were found to contain 8- to 11-fold MDR1 copies and there was no increase in P-glycoprotein expression as compared with R1-5.
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PMID:Activation of silent MDR1 genes in revertant cells by fusion with multidrug-resistant cells. 749 79

The hypothesis that P-glycoprotein (P-gp) mediates the renal secretion of organic cations was tested by functional expression of mRNAs in the Xenopus laevis oocyte system. Efflux of 2'-deoxytubercidin (dTub), a substrate for the renal organic cation transporter (OCT) but not for P-gp, was enhanced by injection of renal mRNA but not by injection of mRNA from P-gp-overexpressing cells (MDCK cells transduced with the cDNA for human MDR1). The functional capacity of the MDCK-MDR mRNA was established by its ability to reduce the steady-state uptake of a classical P-gp substrate, vinblastine. Thus, these data indicate OCT and P-gp to be distinct entities. The Xenopus oocyte system provides a functional approach to further characterize the OCT.
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PMID:Functional expression of the renal organic cation transporter and P-glycoprotein in Xenopus laevis oocytes. 749 91


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