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 have investigated the polarity of the efflux of the intracellular pH fluorochrome 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) from layers of epithelial Madin-Darby canine kidney (MDCK, Strains I and II) and human intestinal (Caco-2, HCT-8 and T84) cells grown on porous membranes. In Strain I MDCK cells, BCECF efflux was effectively reduced by indomethacin (50% inhibition with 100 microM) and 5-nitro-2-(3-phenylpropyl-amino)-benzoate (NPPB; 50% inhibition with 10 microM). Replacement of external Cl- with bromide, iodide or nitrate did not alter BCECF efflux, while substitution with methanesulphonate resulted in a small but significant reduction. All five cell lines form confluent epithelial layers when grown on porous membranes. Efflux of BCECF from Strain I MDCK epithelial layers into the apical solution was approximately three times greater than into the basal solution. Addition of indomethacin to the apical solution attenuated efflux into the apical but not the basal solution, while basal indomethacin was effective against basal efflux. NPPB has a similar specificity of action. Adrenaline, a stimulant of electrogenic Cl- secretion, did not alter the pattern of BCECF efflux. BCECF efflux was also polarized, with apical efflux greater than basal efflux, in MDCK Strain II and Caco-2 epithelial layers. In contrast, BCECF efflux into the basal and apical media was equivalent in layers formed from HCT-8 and T84 cells. However, indomethacin reduced efflux in all five epithelial lines, although the relative sensitivities of the apical and basal efflux rates to indomethacin varied, as did the sensitivity to the sidedness of application of indomethacin. In MDCK and HCT-8 epithelial layers, transepithelial vinblastine secretion mediated by P-glycoprotein was not inhibited by indomethacin. The data are consistent with the hypothesis that BCECF efflux is a manifestation of a novel ATP-dependent xenobiotic secretory efflux mechanism in renal and gastrointestinal epithelia. The factors regulating the polarity of BCECF efflux, both the indomethacin-sensitive and -insensitive components, have yet to be elucidated.
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PMID:Polarized efflux of 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein from cultured epithelial cell monolayers. 151 Jun 94

Exposure of NIH/3T3 fibroblasts not expressing P-glycoprotein to 50, 30, 20, and 10% hyposmotic solutions led to cell volume increases of 70, 32, 21, and 12%, respectively. After swelling, NIH/3T3 cells exhibited regulatory volume decrease (RVD), attaining complete volume recovery after 30 min except in 50% hyposmotic solution, in which volume recovery was 76%. RVD was accelerated by gramicidin and inhibited by the Cl channel blockers 5-nitro-2-(3-phenylpropylamino)-benzoic acid, 1,9-dideoxyforskolin, dipyridamole, and niflumic acid and by the K channel, blocker quinidine. RVD was reduced 15% by removal of extracellular Ca. The pathway opened by hypotonicity was highly permeable to K and Rb and only partly permeable to other cations. Most anions were able to permeate, with a permeability ranking of nitrate > benzoate = iodide > thiocyanate > chloride > > gluconate. The pathway was permeable to neutral amino acids, with a permeability ranking of glycine > alanine > glutamate > taurine > gamma-aminobutyric acid > glutamine. The pathway was not permeable to basic amino acids. These results show that, despite the absence of P-glycoprotein, NIH/3T3 cells exhibit RVD with properties similar to those expressed in most cell types.
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PMID:Volume regulation in NIH/3T3 cells not expressing P-glycoprotein. I. Regulatory volume decrease. 922 7

A population of NG108-15 neuroblastoma cells resistant to doxorubicin (NG/DOXR) was established. The cells exhibited a multidrug resistance phenotype with cross-resistance to vinblastin and colchicine, overexpression of a 170 kDa membrane protein identified as P-glycoprotein and reversal of resistance by verapamil and quinine. Compared with NG108-15 cells, NG/DOXR cells showed an increase in Na+ current density and a decrease in cyclic-AMP-activated Cl- current density with no change in K+- and volume-sensitive Cl- current densities. As previously observed in NG108-15 cells, the vacuolar-type H+-ATPase inhibitors bafilomycin A1 and nitrate induced membrane depolarizations in NG/DOXR cells. The resting potentials of sensitive and resistant cells were not significantly different, but the depolarizations evoked by these agents were significantly larger in NG/DOXR than in NG108-15 cells. The resting membrane potential of NG/DOXR cells, but not that of NG108-15 cells, was depolarized by verapamil, and this effect was abolished by bafilomycin. The volume-sensitive Cl- currents of drug-sensitive and drug-resistant cells were inhibited by a decrease in intracellular pH from 7.3 to 6.8. Whereas bafilomycin prevents activation of Cl- currents in both drug-sensitive and drug-resistant cells, verapamil inhibited the Cl- current only in NG/DOXR cells. The results are discussed in terms of the roles of cytoplasmic pH and membrane potential in multidrug resistance.
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PMID:Alterations of ionic membrane permeabilities in multidrug-resistant neuroblastoma x glioma hybrid cells. 939 Sep 33

The effect of Shiga-like toxin II (SLT-II) (2 microg/animal), which was derived from Escherichia coli O157:H7, on renal handling of levofloxacin (LVX), a model drug for quinolone antimicrobial agents, was investigated in rats 24 h after intravenous injection. In histopathological examination, acute tubular injury was observed in SLT-II-treated rats, but the glomeruli were not injured. SLT-II significantly increased the steady-state concentration of LVX in plasma to 1.5-fold that of control rats. SLT-II induced significant decreases in the glomerular filtration rate (GFR) and renal clearance (CL(R)) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio of p-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-alpha) and nitrite and nitrate (NOx) in plasma. The TNF-alpha inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CL(R) of LVX; in contrast, S-methylisothiourea, a selective inhibitor of inducible nitric oxide synthase, did not. Western blotting analysis revealed that SLT-II did not alter the levels of multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein in kidneys 24 h after injection, assuming the lack of involvement of Mrp2 and P-glycoprotein in SLT-II-induced acute renal tubular injury and renal handling of LVX observed 24 h after SLT-II injection. The present study suggests that SLT-II impairs the renal handling of LVX by decreasing GFR and causing decreased renal plasma flow.
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PMID:Shiga-like toxin II derived from Escherichia coli O157:H7 modifies renal handling of levofloxacin in rats. 1195 91

Grapefruit juice can alter oral drug pharmacokinetics by different mechanisms. Irreversible inactivation of intestinal cytochrome P450 (CYP) 3A4 is produced by commercial grapefruit juice given as a single normal amount (e.g. 200-300 mL) or by whole fresh fruit segments. As a result, presystemic metabolism is reduced and oral drug bioavailability increased. Enhanced oral drug bioavailability can occur 24 hours after juice consumption. Inhibition of P-glycoprotein (P-gp) is a possible mechanism that increases oral drug bioavailability by reducing intestinal and/or hepatic efflux transport. Recently, inhibition of organic anion transporting polypeptides by grapefruit juice was observed in vitro; intestinal uptake transport appeared decreased as oral drug bioavailability was reduced. Numerous medications used in the prevention or treatment of coronary artery disease and its complications have been observed or are predicted to interact with grapefruit juice. Such interactions may increase the risk of rhabdomyolysis when dyslipidemia is treated with the HMG-CoA reductase inhibitors atorvastatin, lovastatin, or simvastatin. Potential alternative agents are pravastatin, fluvastatin, or rosuvastatin. Such interactions might also cause excessive vasodilatation when hypertension is managed with the dihydropyridines felodipine, nicardipine, nifedipine, nisoldipine, or nitrendipine. An alternative agent could be amlodipine. In contrast, the therapeutic effect of the angiotensin II type 1 receptor antagonist losartan may be reduced by grapefruit juice. Grapefruit juice interacting with the antidiabetic agent repaglinide may cause hypoglycemia, and interaction with the appetite suppressant sibutramine may cause elevated BP and HR. In angina pectoris, administration of grapefruit juice could result in atrioventricular conduction disorders with verapamil or attenuated antiplatelet activity with clopidrogel. Grapefruit juice may enhance drug toxicity for antiarrhythmic agents such as amiodarone, quinidine, disopyramide, or propafenone, and for the congestive heart failure drug, carvediol. Some drugs for the treatment of peripheral or central vascular disease also have the potential to interact with grapefruit juice. Interaction with sildenafil, tadalafil, or vardenafil for erectile dysfunction, may cause serious systemic vasodilatation especially when combined with a nitrate. Interaction between ergotamine for migraine and grapefruit juice may cause gangrene or stroke. In stroke, interaction with nimodipine may cause systemic hypotension. If a drug has low inherent oral bioavailability from presystemic metabolism by CYP3A4 or efflux transport by P-gp and the potential to produce serious overdose toxicity, avoidance of grapefruit juice entirely during pharmacotherapy appears mandatory. Although altered drug response is variable among individuals, the outcome is difficult to predict and avoiding the combination will guarantee toxicity is prevented. The elderly are at particular risk, as they are often prescribed medications and frequently consume grapefruit juice.
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PMID:Interactions between grapefruit juice and cardiovascular drugs. 1544 71