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)

A multidrug-resistant Chinese hamster ovary cell line (CR1R12) was obtained which constitutively expresses P-glycoprotein, up to 32% by weight of plasma membrane protein. CR1R12 plasma membranes had high, drug-activated ATPase activity referable to P-glycoprotein. The specific ATPase activity in the presence of verapamil was calculated to be approximately 9 mumol/min/mg (identical to 21 s-1) at 37 degrees C, pH 7.4. KM ATP was 1.4 mM, and ADP and 5'-adenylyl imidodiphosphate were competitive inhibitors with Ki values 0.35 and 0.44 mM, respectively. 2'-dATP was a good substrate, GTP and ITP were real but poor substrates, and ADP and AMP were not hydrolyzed. Optimal pH for ATP hydrolysis was 7.3. MgATP was the preferred substrate, and CaATP was hydrolyzed very weakly. 7-Chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) covalently labeled the P-glycoprotein, and incorporation of 1.1 mol of NBD-Cl/mol of P-glycoprotein gave 100% inactivation. ATP protected against NBD-Cl inactivation. N-Ethylmaleimide was a potent inhibitor in the absence of ATP, and in its presence significant protection from inhibition could be achieved. Vanadate and fluoroaluminate were also strong inhibitors. The plasma membranes from CR1R12 cells should provide material for purification and reconstitution of P-glycoprotein and for screening of potential "multidrug-reversal" reagents by enzymic assay.
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PMID:Characterization of the adenosine triphosphatase activity of Chinese hamster P-glycoprotein. 809 47

These studies examined the ability of ATP to stimulate transport of the organic cation tetraethylammonium (TEA) into proximal tubular brush border membrane vesicles. ATP markedly enhanced TEA uptake for 1 h or more to values severalfold above those observed in the absence of ATP. The poorly hydrolyzable analogue of ATP, AMP-PNP (adenyl-5'-yl imidodiphosphate), reduced the effect of ATP but alone did not stimulate TEA uptake. GTP and ITP also stimulated TEA uptake, whereas other nucleotides did not. ATP-stimulated TEA uptake was saturable, temperature-dependent, and markedly reduced by the organic cations amiloride, quinidine, cimetidine, and verapamil, but only modestly reduced by the organic cations N'-methylnicotinamide and choline. Some inhibitors of other transport ATPases, including N-ethylmaleimide, N,N'-dicyclohexylcarbodiimide, and oligomycin, reduced the effect of ATP, whereas ouabain, vanadate, and azide did not. 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid also reduced TEA uptake in the presence of ATP. Vinblastine, but not actinomycin D and colchicine (all inhibitors of P-glycoprotein-mediated transport), reduced TEA uptake. The reduction of TEA transport by amiloride and cimetidine was most consistent with competitive inhibition, whereas the inhibition produced by N-ethylmaleimide and vinblastine evidently was not. ATP also stimulated uptake of N'-methylnicotinamide but not that of vinblastine. These studies have identified a previously unrecognized process by which ATP hydrolysis may directly energize the reabsorption of organic cations from the renal tubule lumen.
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PMID:ATP-stimulated tetraethylammonium transport by rabbit renal brush border membrane vesicles. 846 19

Studies have suggested that high P-glycoprotein expression in lymphocytes from patients with autoimmune disorders may affect disease outcome. Idiopathic thrombocytopenic purpura (ITP) and Evans' syndrome are widely thought to be autoimmune processes, however, the precise mechanisms remain unknown. Peripheral blood mononuclear cells from patients with refractory or recurrent ITP or Evans' syndrome were studied using the rhodamine 123 flow cytometric assay to investigate functional export levels. Lymphocytes from ITP and Evans' syndrome patients showed a significantly decreased ability to retain rhodamine, suggesting increased export protein function. Reverse transcription polymerase chain reaction distinguished P-glycoprotein as the likely export protein.
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PMID:High P-glycoprotein-mediated export observed in patients with a history of idiopathic thrombocytopenic purpura. 1218 Oct 55

High P-glycoprotein-mediated multidrug resistance-1 (P-gp/MDR1) activity in lymphocytes from idiopathic thrombocytopenic purpura (ITP) patients may affect disease outcome. ITP treatment includes glucocorticoids that are substrates of P-gp; hence, P-gp functional activity and antigenic expression were assessed by flow cytometry in T and natural killer (NK) cells from ITP patients before and after prednisone therapy. Herein, patients' T and NK cells did not show increased MDR1 functional activity, whereas P-gp antigenic expression was significantly enhanced in both therapy-free and prednisone-treated patients. Prednisone treatment did not significantly modify the function and expression of MDR1 in T and NK cells of ITP patients.
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PMID:Multidrug resistance-1 in T lymphocytes and natural killer cells of adults with idiopathic thrombocytopenic purpura: effect of prednisone treatment. 1851 1

Resistance to glucocorticoids (GCs) remains a tricky problem complicating the therapy of ITP. Recently, ATP binding cassette gene B1 gene (ABCB1) was reported to be correlated with susceptibility and therapeutic efficacy of autoimmune diseases through P-glycoprotein (Pgp). We investigated three single nucleotide polymorphisms (SNPs) of ABCB1 and their haplotypes by PCR-RFLP (restriction fragment length polymorphism) method in 471 ITP patients and 383 healthy controls, patients were further assigned into GCs-responsive and -non-responsive group according to the therapeutic effects of GCs. We observed a remarkable difference in genotypes of G2677T/A between GCs-responsive and non-responsive group, but not between patients and controls. A frequently expression of T/A allele within G2677T/A was recorded in GCs-responsive group. Furthermore, we found that some haplotypes (CGC, CTC/CAC, CTT/CAT, TGC, TGT, TTC/TAC and TTT/TAT, in the order of position 1236-2677-3435) were presented significantly differences between non-responsive and responsive group. No difference of C1236T and C3435T polymorphisms was observed between ITP and controls, and between the GCs-responsive and -non-responsive group. Our findings suggest that ABCB1 polymorphisms, as well as haplotypes derived from C1235T, G2677T/A and C3435T, are associated with inter-individual differences of GCs treatment in ITP.
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PMID:Association of ABCB1 gene polymorphisms and haplotypes with therapeutic efficacy of glucocorticoids in Chinese patients with immune thrombocytopenia. 2448 77