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)

On the basis of physiological localization, broad substrate specificity and energy dependence, the role of the kidney P-glycoprotein was tested in the energy-dependent renal secretion of organic cations. P-glycoprotein-enriched vesicles from Cl 1D/VCR [a multidrug-resistant (MDR) cell line] displayed enhanced transport of the MDR drug vinblastine and the organic cation cimetidine but not of the organic cation tetraethylammonium (TEA) over that shown by vesicles prepared from the drug-sensitive parental line Cl 1D. An outwardly directed proton gradient stimulated TEA and cimetidine uptake by renal brush border membrane vesicles (BBMV) but this gradient did not enhance the uptake of these organic cations into Cl 1D/VCR vesicles. Vinblastine uptake was unaffected by the proton gradient in either vesicle preparation. An outwardly directed gradient of TEA enhanced the uptake of TEA into renal BBMV but did not do so in the case of Cl 1D/VCR vesicles. These data indicate that P-glycoprotein, which is normally energized by ATP hydrolysis, is incapable of catalyzing organic cation/proton exchange or organic cation/organic cation exchange, properties of the organic cation carrier of renal proximal tubule BBMV. The MDR substrates and modulators inhibited the uptake of vinblastine and cimetidine by Cl 1D/VCR vesicles and the uptake of cimetidine and TEA by renal BBMV. Several organic cations studied inhibited TEA and cimetidine uptake by renal BBMV but did not inhibit the uptake of vinblastine and cimetidine by Cl 1D/VCR vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:P-glycoprotein and organic cation secretion by the mammalian kidney. 791 80

Cimetidine has been used as a relatively selective inhibitor of renal organic cation secretion, analogous to the use of probenecid to inhibit organic anion secretion. Many of the substrates for the multidrug transporter P-glycoprotein, which is overexpressed in multidrug-resistant tumor cells, are organic cations. Furthermore, the protein is normally expressed on the apical membranes of proximal tubule cells, the postulated site for active organic cation secretion. To test directly whether P-glycoprotein might serve as a carrier for cimetidine, we measured cimetidine transepithelial movement across Madin-Darby canine kidney cells grown as monolayers on membrane filters. A retrovirally transduced Madin-Darby canine kidney cell line (Madin-Darby canine kidney cells transfected with the human multiple drug resistance 1 cDNA for P-glycoprotein), that expresses the human form of P-glycoprotein on its apical membrane, had an increased capacity to transport cimetidine from the basolateral to apical medium (b-->a) but not in the reverse direction (i.e., a-->b). Qualitatively similar results were observed with daunomycin, a well established substrate for P-glycoprotein. Cellular uptake and energy-dependent efflux experiments further established cimetidine to be a substrate for the human P-glycoprotein. Thus, P-glycoprotein may play a role in the renal secretion of cimetidine and perhaps other organic cations.
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PMID:Enhanced transepithelial flux of cimetidine by Madin-Darby canine kidney cells overexpressing human P-glycoprotein. 791 94

Multidrug resistance (MDR) to chemically unrelated therapeutic anticancer agents in mammalian cells is mediated by the overexpression of an ATP-dependent 150- to 180-kD membrane glycoprotein P-glycoprotein (P-gp). Although the complete physiological role of P-gp is unknown, it is proposed to function in cellular detoxification of xenobiotics. In this study, we investigated whether the organophosphorus insecticide chlorpyrifos (O,O-diethyl O-3,5,6-trichloro-2-pyridinyl phosphorothioate) or its metabolites interact with P-gp. Immunohistochemical analysis of tissues from male Fischer 344 rats administered chlorpyrifos (7.6 mg/kg gavage) showed increased P-gp expression in the kidney, adrenal, liver, jejunum, and stomach (tissues associated with elimination of xenobiotics), compared to control tissues. The most prominent increase was detected in the large bile ducts of the liver and the proximal tubule region of the kidney. P-gp expression was increased throughout the adrenal medulla and cortex, while a moderate increase was detected in the epithelial layers of the stomach and jejunum. To examine further the interaction between chlorpyrifos and P-gp, we evaluated whether chlorpyrifos or its active metabolite, chlorpyrifos oxon, could inhibit [3H]azidopine labeling of P-gp in MDR1 baculovirus-infected insect Sf9 cells. A concentration-dependent inhibition of [3H]azidopine labeling of P-gp was detected with chlorpyrifos oxon, while significant inhibition was not detected with chlorpyrifos. To correlate the binding of chlorpyrifos oxon to P-gp with a biochemical effect, we examined its ability to stimulate P-gp-mediated ATPase activity in these Sf9 cells. Chlorpyrifos oxon stimulated P-gp ATPase activity 1.75 times that of the positive control (10 microM verapamil). Taken together, these results suggest that chlorpyrifos oxon interacts with P-gp, and support the hypothesis that P-gp may play a role in the cellular detoxification of insecticides in mammalian tissues. To our knowledge this is the first report of an organophosphorus insecticide interacting with and increasing the expression of P-gp.
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PMID:Chlorpyrifos oxon interacts with the mammalian multidrug resistance protein, P-glycoprotein. 860 Feb 91

P-glycoprotein (PGP), which confers multidrug resistance to cancer cells, is expressed in mouse kidney proximal tubule and mesangium. We report on the expression of PGP and its xenobiotic transport function in mesangial cells. Studies were performed in a mouse mesangial cell line (TKGM) and two cell clones. Ribonuclease protection assay and Western blot analysis demonstrated that TKGM cells expressed mdr1 and mdr3, the isoforms responsible for multidrug resistance. TKGM-F12 cells coexpressed mdr1 and mdr3 whereas TKGM-G2 cells expressed only mdr1. The drug transport function, measured by rhodamine 123 (R-123) efflux, was smaller in TKGM-F12 than in TKGM-G2 cells. The PGP substrates adriamycin, cyclosporin A, vinblastine, and verapamil inhibited R-123 transport in TKGM and TKGM-G2 cells. In the cells studied, PGP conferred some resistance to adriamycin; concomitant exposure to adriamycin with another PGP substrate impaired cell growth. The differential expression of mdr1 and mdr3 in mouse mesangial cell clones, the ability of mdr1 PGP to transport R-123, and the impairment of PGP-mediated transport in TKGM-F12 cells, coexpressing mdr1 and mdr3 products, are demonstrated. PGP may play a physiological role in mesangial cells.
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PMID:Xenobiotic transport differences in mouse mesangial cell clones expressing mdr1 and mdr3. 863 74

1. Previous studies have shown that the weak base, cimetidine, is actively secreted by the renal proximal tubule. In this study we have examined the transport of cimetidine by renal LLC-PK1 epithelial cell monolayers. 2. In LLC-PK1 cell monolayers the basal-to-apical flux of cimetidine was significantly greater than the apical-to basal flux, consistent with net secretion of cimetidine in a basal-to-apical direction. 3. Net secretion of cimetidine was significantly (70%) reduced by the addition of either 100 microM verapamil or 100 microM nifedipine to the apical membrane. The reduction in net secretion was the result of an inhibition of basal-to-apical flux; these agents had no effect upon flux in the apical-to-basal direction. These results suggest that cimetidine secretion is mediated primarily by P-glycoprotein located in the apical membrane. In addition we found no evidence of a role for organic cation antiport in the secretion of cimetidine. 4. In the presence of an inwardly directed proton gradient across the apical membrane (pH 6.0), cimetidine secretion was significantly reduced compared to that measured at an apical pH of 7.4. The reduction in net secretion at pH 6.0 was the result of a stimulation of cimetidine uptake across the apical membrane. This pH-dependent uptake mechanism was sensitive to inhibition by DIDS (100 microM). 5. Experiments with BCECF (2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein) loaded monolayers demonstrated that cimetidine influx across the apical membrane was associated with proton flow into the cell and was sensitive to inhibition by DIDS. 6. These results suggest that net secretion of cimetidine across the apical membrane is a function of the relative magnitudes of cimetidine secretion mediated by P-glycoprotein and cimetidine absorption mediated by a novel proton-coupled, DIDS-sensitive transport mechanism.
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PMID:Mediation of cimetidine secretion by P-glycoprotein and a novel H(+)-coupled mechanism in cultured renal epithelial monolayers of LLC-PK1 cells. 888 8

Renal drug elimination involves three major processes: glomerular filtration, tubular secretion, and tubular reabsorption. Drug filtration is a simple unidirectional diffusion process. Renal tubular secretion and reabsorption are bidirectional processes that often involve both passive diffusion and carrier-mediated membrane processes. Various in vivo and in vitro techniques are available to study renal drug elimination and renal drug transport. The complete renal handling of a drug is best understood from data obtained from a combination of in vivo and in vitro methodologies. At the membranes of the renal proximal tubule, a number of carrier systems are involved in the tubular secretion and/or reabsorption of various drugs. Organic acid and base transporters are two major carrier systems important in the tubular transport of a number of organic acid and base drugs, respectively. Nucleoside and P-glycoprotein transporters appear to play an important role in renal tubular transport of dideoxynucleosides (e.g., zidovudine, dideoxyinosine) and digoxin, respectively. Clinically, these transporters are not only necessary for the renal tubular secretion and reabsorption of various drugs, but are also responsible in part for the drug's pharmacologic response (e.g., furosemide), drug-drug interactions of therapeutic or toxic importance, and drug nephrotoxicity.
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PMID:Renal drug transport: a review. 894 68

In normal tissues, P-glycoprotein(P-gp), which is expressed in various tumor cells, is found on the luminal surface of epithelia of the kidney proximal tubule, small intestine and colon and bile canalicular face of hepatocytes, as well as, in the adrenal and capillary endothelial cells in the brain and testis. The physiological function of P-gp remains unclear but growing amounts of information suggest that it can play a important role in the absorption from intestine, elimination from liver and kidney and distribution into brain across the blood-brain barrier for many cancer chemotherapeutic agents as well as other drugs which reverse multidrug resistance. The competition for the P-gp-mediated transports in tissues and organs, which express multidrug-transporter, might lead to unsuspected drug interactions among these drugs.
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PMID:[Tissue distribution of the multidrug-resistance gene product P-glycoprotein and its physiological function]. 915 53

Intrinsic and acquired multidrug resistance (MDR) in many human cancers may be due to expression of the multidrug transporter P-glycoprotein (Pgp), which is encoded by the mdr1 gene. There is substantial evidence that Pgp is expressed both as an acquired mechanism (e.g., in leukemias, lymphomas, myeloma, and breast and ovarian carcinomas) and constitutively (e.g., in colorectal and renal cancers) and that its expression is of prognostic significance in many types of cancer. Clinical trials of MDR modulation are complicated by the presence of multiple-drug-resistance mechanisms in human cancers, the pharmacokinetic interactions that result from the inhibition of Pgp in normal tissues, and, until recently, the lack of potent and specific inhibitors of Pgp. A large number of clinical trials of reversal of MDR have been undertaken with drugs that are relatively weak inhibitors and produce limiting toxicities at doses below those necessary to inhibit Pgp significantly. The advent of newer drugs such as the cyclosporin PSC 833 (PSC) provides clinicians with more potent and specific inhibitors for MDR modulation trials. Understanding how modulators of Pgp such as PSC 833 affect the toxicity and pharmacokinetics of cytotoxic agents is fundamental for the design of therapeutic trials of MDR modulation. Our studies of combinations of high-dose cyclosporin (CsA) or PSC 833 with etoposide, doxorubicin, or paclitaxel have produced data regarding the role of Pgp in the clinical pharmacology of these agents. Major pharmacokinetic interactions result from the coadministration of CsA or PSC 833 with MDR-related anticancer agents (e.g., doxorubicin, daunorubicin, etoposide, paclitaxel, and vinblastine). These include increases in the plasma area under the curve and half-life and decreases in the clearance of these cytotoxic drugs, consistent with Pgp modulation at the biliary lumen and renal tubule, blocking excretion of drugs into the bile and urine. The biological and medical implications of our studies include the following. First, Pgp is a major organic cation transporter in tissues responsible for the excretion of xenobiotics (both drugs and toxins) by the biliary tract and proximal tubule of the kidney. Our clinical data are supported by recent studies in mdr-gene-knockout mice. Second, modulation of Pgp in tumors is likely to be accompanied by altered Pgp function in normal tissues, with pharmacokinetic interactions manifesting as inhibition of the disposition of MDR-related cytotoxins (which are transport substrates for Pgp). Third, these pharmacokinetic interactions of Pgp modulation are predictable if one defines the pharmacology of the modulating agent and the combination. The interactions lead to increased toxicities such as myelosuppression unless doses are modified to compensate for the altered disposition of MDR-related cytotoxins. Fourth, in serial studies where patients are their own controls and clinical resistance is established, remissions are observed when CsA or PSC 833 is added to therapy, even when doses of the cytotoxin are reduced by as much as 3-fold. This reversal of clinical drug resistance occurs particularly when the tumor cells express the mdr1 gene. Thus, tumor regression can be obtained without apparent increases in normal tissue toxicities. In parallel with these trials, we have recently demonstrated in the laboratory that PSC 833 decreases the mutation rate for resistance to doxorubicin and suppresses activation of mdr1 and the appearance of MDR mutants. These findings suggest that MDR modulation may delay the emergence of clinical drug resistance and support the concept of prevention of drug resistance in the earlier stages of disease and the utilization of time to progression as an important endpoint in clinical trials. Pivotal phase III trials to test these concepts with PSC 833 as an MDR modulator are under way or planned for patients with acute myeloid leukemias, multiple myeloma, and ovarian carcinoma.
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PMID:Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. 927 28

P-glycoprotein (Pgp), the product of the multidrug resistance (MDR) gene overexpressed in cancer cells, is present also in normal tissues. In the kidney, MDR1 Pgp has been found in the proximal tubule and in cultured mesangial cells. In situ hybridization and immunohistochemistry were used to determine the complete nephronal localization of MDR mRNA and its product, Pgp, in the human kidney. MDR mRNA expression was studied with the use of nonradioactive in situ MDR RNA probes. MDR1 Pgp was immunolocalized using the specific monoclonal antibody MRK16. The presence of MDR mRNA was confirmed in proximal tubules and mesangium, and demonstrated as well in thick limb of Henle's loops and in collecting ducts. MDR1 Pgp colocalized in the same nephronal segments. This suggests that, in addition to secreting xenobiotics, Pgp may play a role in the transport of endogenous substrates or in the regulation of Cl- channels.
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PMID:Expression of MDR1 (multidrug resistance) gene and its protein in normal human kidney. 937 21

There is a renewed attention on the multidrug resistance genes and their products, P-glycoproteins, since recent molecular and functional studies revealed unexpected functions in normal tissues. There are two types of human P-glycoprotein: Type I, encoded by the MDR1 gene, present in excretory organs and in non-polarized cells; and Type II, encoded by MDR2, present in the canalicular membrane of hepatocytes. MDR1 Pgp transports xenobiotics, peptides, steroids, and phospholipids, and is also a regulator of swelling-activated chloride channels. MDR2 Pgp is exclusively a phosphatidylcholine translocase. In the kidney, the MDR1 gene and protein are expressed in mesangial, proximal tubule, thick loop of Henle, and collecting duct cells. In mesangial and proximal tubule cells Pgp transports xenobiotics. Concomitant exposure of kidney cells to two Pgp substrates results in increased cell toxicity. Extracts from supernatants of mesangial cell cultures inhibit Pgp-mediated transport, suggesting that a mesangial-cell metabolite could be a substrate of Pgp. Active vitamin D3 and platelet activating factor inhibit Pgp transport and are possible endogenous substrates in proximal tubule and mesangial cells, respectively. Pgp could be also a regulator of swelling-activated chloride channels present in the kidney.
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PMID:P-glycoprotein functions and substrates: possible roles of MDR1 gene in the kidney. 955 26


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