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)

Antiprogestins represent a relatively new and promising class of therapeutic agents that could have significant impact on human health and reproduction. In the present work, the pharmacodynamics, pharmacokinetics, and metabolism of mifepristone (MIF), lilopristone (LIL), and onapristone (ONA) in humans are reviewed, and characteristics bearing important clinical implications are discussed. Although MIF has gained notoriety as an "abortion pill," antiprogestins may more importantly prove effective in the treatment of endometriosis, uterine leiomyoma, meningioma, cancers of the breast and prostate, and as contraceptive agents. MIF pharmacokinetics display nonlinearities associated with saturable plasma protein (alpha 1-acid glycoprotein, AAG) binding and characterized by lack of dose dependency for parent drug plasma concentrations (for doses greater than 100 mg) and a zero-order phase of elimination. LIL and ONA pharmacokinetics are less well characterized but ONA does not appear to bind AAG and displays a much shorter t1/2 than the other agents. The three antiprogestins are substrates of cytochrome P450 (CYP) 3A4, an enzyme exceedingly important in human xenobiotic metabolism. Even more implicative of likely drug-drug interactions subsequent to their long-term administration are recent data from our laboratory indicating that they inactivate CYP3A4 in a cofactor- and time-dependent manner, suggesting that complexation and induction of the enzyme may occur in vivo via protein stabilization. Moreover, it has been demonstrated that MIF increases CYP3A4 mRNA levels in human hepatocytes in primary culture, indicative of message stabilization and/or transcriptional activation of CYP3A4 expression. Finally, MIF has also been shown to inhibit P-glycoprotein function. Whether LIL and ONA share these latter two characteristics with MIF has not yet been determined but they illustrate properties that, in addition to diminished antiglucocorticoid activities and altered pharmacokinetic characteristics, warrant consideration during the development of these and never antiprogestational agents.
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PMID:Antiprogestin pharmacodynamics, pharmacokinetics, and metabolism: implications for their long-term use. 969 76

Mammalian liver exhibits expression of members of the family of multidrug resistance (mdr) transporters (P-glycoproteins). P-glycoprotein isoforms encoded by mdr1 genes participate in extrusion of an array of xenobiotics into the bile. Induction of mdr1b mRNA expression has been shown to occur in rat hepatocytes in response to hepatotrophic growth factors. As the cytokine tumor necrosis factor alpha (TNF-alpha) is known to exert a direct mitogenic effect on hepatocytes, its influence on mdr1b expression was investigated. In primary rat hepatocytes cultured in the absence of TNF-alpha, a time-dependent increase in basal expression of mdr1b mRNA and in immunodetectable P-glycoprotein was observed. In cells treated with TNF-alpha (4,000 U/ml) for 3 days, expression of mdr1b mRNA and of immunodetectable P-glycoprotein was induced approximately twofold. Moreover, intracellular steady-state levels of the mdr1 substrate rhodamine 123 were decreased in cells pretreated with TNF-alpha in comparison to controls, indicating an increase in functional transporter(s) mediating dye extrusion. Treatment of hepatocytes with antioxidants (1 mM ascorbic acid and 2% dimethyl sulfoxide) for 3 days markedly suppressed mdr1b mRNA and P-glycoprotein expression both in cells cultured in the presence of TNF-alpha and in the absence of the cytokine, but did not fully abolish mdr1b mRNA induction by TNF-alpha, supporting the notion that reactive oxygen species participate in regulation of basal mdr1b gene expression during hepatocyte culture. In conclusion, the present data indicate that by inducing mdr1b expression in hepatocytes, TNF-alpha may affect the capacity of the liver for extrusion or detoxification of endogenous or xenobiotic mdr1 substrates.
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PMID:Induction of mdr1b mRNA and P-glycoprotein expression by tumor necrosis factor alpha in primary rat hepatocyte cultures. 969 3

Marine elasmobranch rectal gland is a specialized, osmoregulatory organ composed of numerous blind-ended, branched tubules emptying into a central duct. To date, NaCl excretion has been its only described function. Here we use isolated rectal gland tubule fragments from dogfish shark (Squalus acanthias), fluorescent xenobiotics, and confocal microscopy to describe a second function, xenobiotic excretion. Isolated rectal gland tubules rapidly transported the fluorescent organic anion sulforhodamine 101 from bath to lumen. Luminal accumulation was concentrative, saturable, and inhibited by cyclosporin A (CSA), chlorodinitrobenzene, leukotriene C4, and KCN. Inhibitors of renal organic anion transport (probenecid, p-aminohippurate), organic cation transport (tetraethylammonium and verapamil), and P-glycoprotein (verapamil) were without effect. Cellular accumulation of sulforhodamine 101 was not concentrative, saturable, or inhibitable. Rectal gland tubules did not secrete fluorescein, daunomycin, or a fluorescent CSA derivative. Finally, frozen rectal gland sections stained with an antibody to a hepatic canalicular multispecific organic anion transporter (cMOAT or MRP2) showed heavy and specific staining on the luminal membrane of the epithelial cells. We conclude that rectal gland is capable of active and specific excretion of xenobiotics and that such transport is mediated by a shark analog of MRP2, an ATP-driven xenobiotic transporter, but not by P-glycoprotein.
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PMID:Excretory transport of xenobiotics by dogfish shark rectal gland tubules. 972 65

A membrane associated ATP-dependent efflux pump, similar in function to mammalian P-glycoprotein, was detected in anal papillae of Chironomus riparius larvae. Immunohistochemical analysis of larval tissues, using monoclonal antibodies against P-glycoprotein, was supplemented by functional in vivo and in vitro assays which confirmed the existence of a mechanism for transporting xenobiotic substances. The in vitro ATPase activity of homogenate fractions increased in the presence of typical P-glycoprotein substrates (vinblastine, actinomycin D or ivermectin). This increase was unaffected by inhibitors of other membrane ATPases (sodium azide, EGTA, ouabain), but sensitive to vanadate, cyclosporin A and verapamil which inhibit mammalian P-glycoprotein mediated ATP-consumption. Sublethal concentrations of specific P-glycoprotein-inhibitors such as verapamil or cyclosporin A synergistically enhanced the mortality of C. riparius towards ivermectin. Although cyclosporin A originates from entomopathogenic fungi, its mode of action in insects and its function during infection are not understood. Our results lend some credit to the hypothesis that this compound is possibly released to promote poisoning of the infected host by xenobiotics which are normally removed by a P-glycoprotein related pump. The putative role of insect P-glycoprotein homologues in the context of multiple resistance towards insecticides in discussed.
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PMID:Detection of a P-glycoprotein related pump in Chironomus larvae and its inhibition by verapamil and cyclosporin A. 997 16

P-glycoprotein can extrude a variety of structurally diverse, toxic xenobiotic compounds from cells. It is believed to be one of key molecules which can cause multidrug resistance in cancer. This paper deals with recent progress in P-glycoprotein research, especially in its structure, mechanisms for substrate recognition and transport. The review also discusses specific modulators of multidrug resistance in cancer and gene therapy using the MDR1 gene.
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PMID:Recent progress in P-glycoprotein research. 1040 38

In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ET(B) receptor antagonist but not by an ET(A) receptor antagonist. Immunostaining with an antibody to mammalian ET(B) receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ET(B) receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.
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PMID:Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule. 1061 79

Rifampicin, an antibiotic widely used in tuberculosis therapy, is known to exert psychotropic side effects in some patients. Recently, rifampicin has been reported to activate the glucocorticoid receptor (GR) in human hepatocytes. Because there is evidence that increased levels of glucocorticoids may induce cognitive impairment, sometimes culminating in depression, the side effects of rifampicin may result from GR activation in central nerve cells. Therefore, we used reporter gene assays to determine whether rifampicin displays glucocorticoid-like effects in human neuroblastoma SK-N-MC cells or mouse hippocampal HT22 cells. Rifampicin was unable to elicit any detectable transactivation of GR in both cell types, whereas cortisol or dexamethasone led to a potent transcriptional response. Rifampicin was also inactive in the same HepG2 cell line that was originally used to demonstrate the effect of rifampicin on GR. Moreover, rifampicin was unable to compete with dexamethasone for binding to GR. Finally, by blocking the multidrug resistance P-glycoprotein transporter (a xenobiotic extrusion pump) with verapamil or cyclosporin A, we excluded the possibility that the lack of effect by rifampicin was due to its export from the cell. Our results establish that rifampicin does not activate GR, and rule out the hypothesis that the psychotropic side effects of rifampicin treatment are a consequence of GR activation.
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PMID:Rifampicin is not an activator of glucocorticoid receptor. 1072 19

Xenobiotic resistance in animals, plants, yeast, and bacteria is known to involve ATP binding cassette transporters that efflux invading toxins. We present data from yeast and a higher plant indicating that xenobiotic resistance also involves extracellular ATP degradation. Transgenic upregulation of ecto-ATPase alone confers resistance to organisms that have had no previous exposure to toxins. Similarly, cells that are deficient in extracellular ATPase activity are more sensitive to xenobiotics. On the basis of these and other supporting data, we hypothesize that the hydrolysis of extracellular ATP by phosphatases and ATPases may be necessary for the resistance conferred by P-glycoprotein.
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PMID:A role for ectophosphatase in xenobiotic resistance. 1076 Feb 41

The aim of this study was to investigate the role of P-glycoprotein (P-gp) in the adrenal gland. It has been presumed that P-gp, rather than being involved in physiological cortisol secretion, plays a role in protecting the adrenacortical cells from xenobiotics. To explore this a study was performed on perfused bovine adrenal glands. Individual experimental groups were perfused with either a selective P-gp blocker (valspodar) alone, with a xenobiotic (mitotane or doxorubicin) alone or with both valspodar and a xenobiotic. The cumulative amounts of cortisol secreted in each individual group were calculated and the two-sample t-test was used to compare the mean values of cumulative amounts. The mean value of cortisol secreted from the group of adrenals perfused with the P-gp blocker was not significantly different from that of the control group. Treatment with either mitotane or doxorubicin decreased the amount of cortisol secreted but not significantly when compared to the amount of cortisol secreted in basal conditions. However, treatment with the P-gp blocker valspodar in addition to either mitotane or doxorubicin significantly decreased cortisol secreted compared to the amount of cortisol secreted by the glands treated with either mitotane (p=0.009) or doxorubicin (p=0.017) alone. The regressive changes discovered in all experimental groups were most prominent when valspodar was used with either mitotane or doxorubicin. We found that P-gp blockade increases by xenobiotic (mitotane and doxorubicin)-induced damage of adrenocortical cells, which points to a role of P-gp in the protection of adrenal gland from xenobiotics.
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PMID:Decreased cortisol secretion by adrenal glands perfused with the P-glycoprotein inhibitor valspodar and mitotane or doxorubicin. 1089 47

The effects of xenobiotic drugs and toxic compounds depend largely on their kinetic properties, which can be influenced by transmembrane drug transporters like MDR1/P-glycoprotein and the drug-conjugate transporters multidrug resistance protein (MRP) 1 and 2. As the dog is a preferential species used in the pharmacological and toxicological evaluation of new drugs, we sequenced the canine MRP2 cDNA and investigated its expression in various canine tissues compared with the related transporters MRP1 and P-glycoprotein. The tissue distribution pattern of these ABC-transporters differs partially from the distribution described in humans. So we found relatively high renal and low hepatic canine MRP2 expression levels, relatively high hepatic canine MRP1 expression levels, and quite high levels of MRP1 and P-glycoprotein in the dog brain. The knowledge of the tissue distribution pattern of these transporters will aid to interpret pharmacokinetic and toxicokinetic data gained from dog studies and to extrapolate them to humans.
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PMID:Sequencing and tissue distribution of the canine MRP2 gene compared with MRP1 and MDR1. 1116 10


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