Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance (MDR) mechanisms have been widely studied in cancer. Among them, P-glycoprotein (P-gp) overfunction has been associated with resistance to several antineoplastic agents. The physiological role of P-gp involves hormone and metabolite secretion, bacterial product detoxification, and transport of several drugs to the extracellular space, thus inhibiting their toxic or therapeutic effects. The study of MDR-1 in diseases of autoimmune origin has just recently emerged. Corticosteroids remain the mainstay therapy for autoimmune diseases. As prednisone (PDN) is transported by P-gp, the aim of this study was to evaluate the P-gp function in lymphocytes from myasthenia gravis (MG) patients. Thirty MG patients and 25 healthy controls were studied. Peripheral blood mononuclear cells were isolated by gradient centrifugation and incubated with daunorubicin (DNR) (a fluorescent drug extruded by P-gp). Functional activity of P-gp was analyzed by flow cytometry. Results were expressed as percentage of gated lymphocytes able to efflux DNR. Overall, MG patients showed increased numbers of lymphocytes with functional P-gp activity when compared with controls (x = 4.92 +/- 5.26% vs. x = 0.7 +/- 0.48%, respectively) (P < 0.0001). When patients were classified as responders (n = 21) or refractory (n = 9) to treatment, the latter group exhibited higher values of functional P-gp (x = 10.18 +/- 6.39%) when compared to the responder group (x = 2.66 +/- 2.45%) (P = 0.0076). These data suggest, on the one hand, that drug resistance may be induced by long-term treatment or by high PDN doses and, on the other, emphasize the need for the study of P-gp antagonists in order to improve the current therapeutical schemes for the treatment of MG.
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PMID:Multidrug resistance-1 (MDR-1) in autoimmune disorders IV. P-glycoprotein overfunction in lymphocytes from myasthenia gravis patients. 1519 68

Tacrolimus hydrate (FK506) reduces the symptoms of myasthenia gravis (MG) due to its immunosuppressive properties. A drug efflux pump P-glycoprotein (P-gp) actively transports FK506 out of target cells, thereby reducing their efficacy. We investigated the influence of FK506 therapy on the P-gp function of peripheral-blood mononuclear cells (PBMCs) in MG patients. Six MG patients treated with FK506 (MG(FK+)), four MG patients treated without FK506 administration (MG(FK-)), and 18 healthy subjects were included in this study. P-gp function was estimated by transporter activity that was inferred from a decrease in fluorescent P-gp substrate Rhodamine 123 (Rh123) and its inhibition by cyclosporine A (CsA). The P-gp efflux function in MG (FK+) patients assessed by the Kolmogorov-Smirnov (KS) statistic D was lower than in the healthy subjects (p=0.0084). However, PBMC sensitivity to FK506 in MG (FK+) patients was significantly higher compared to that of the healthy subjects (p=0.02). There was a significant correlation between the Rh123 efflux activity and PBMC sensitivity to FK506 in vitro (p=0.011). The data raise the possibility that FK506 treatment attenuated P-gp function in the PBMCs of the MG patients.
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PMID:P-glycoprotein function in peripheral blood mononuclear cells of myasthenia gravis patients treated with tacrolimus. 1726 68

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder with a chronic clinical course that requires long-term glucocorticoid (GC) therapy. A drug efflux pump, P-glycoprotein (P-gp), actively transports GC out of target cells, thereby reducing its efficacy. We evaluated the P-gp function of peripheral-blood mononuclear cells in 59 MG patients. P-gp function was estimated from a decrease in fluorescent P-gp substrate Rhodamine 123 and its inhibition by the conformation-sensitive UIC2 monoclonal antibody. P-gp function on CD8(+) T cells in 21 MG patients having experienced GC therapy was higher than that in 19 MG patients having no history of GC therapy (p=0.026). There was a significant correlation between P-gp function in CD3(+) (r=0.55, p=0.014) or CD4(+) (r=0.48, p=0.034) T cells and the total dose of prednisolone for treatment. P-gp function on CD4(+) T cells in MG patients who showed low responses to prednisolone therapy (n=8) was higher than that in patients who showed relatively high responses to prednisolone therapy (n=10) (p=0.045). These results suggest that higher P-glycoprotein activity on CD3(+) or CD4(+) cells necessitated treatment with higher steroid doses in order to achieve a clinical response. The measurement of P-gp function on CD4(+) T cells is useful in the assessment of clinical response to GC therapy.
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PMID:P-glycoprotein function in peripheral T lymphocyte subsets of myasthenia gravis patients: clinical implications and influence of glucocorticoid administration. 1910 57

Myasthenia gravis is an autoimmune disorder mediated by antibodies against the acetylcholine receptors of the skeletal muscles. Imbalances between T helper type 1 and type 2 cytokine production play a key role in the induction and development of several autoimmune diseases. Peripheral T helper type 1 and type 2 cells in 50 myasthenia gravis patients were estimated by intracellular cytokines. The percentage of T helper type 1 cells in CD4(+) cells was higher than that of type 2 or type 0 cells (P<0.0001). There was a significant correlation between T helper type 1/type 2 ratio and the P-glycoprotein function on CD3(+) T cells (P=0.008). In the patients treated with prednisolone alone (n=12), there was a significant correlation negatively between the percentage of change in the T helper type 1/type 2 ratio and the reduction rate of quantitative myasthenia gravis scores after 12 months of treatment (P=0.012). In contrast, all of the patients treated with prednisolone and calcineurin inhibitor in combination saw reductions in the scores. Our data suggest that the T helper type 1/type 2 ratio was involved in the disease activity of the patients treated with prednisolone alone. On the other hand, the patients treated with prednisolone and calcineurin inhibitor in combination had their disease condition improved regardless of the T helper type 1 predominance. Therefore, the data suggest that supplemental calcineurin inhibitors are effective for the myasthenia gravis patients treated with prednisolone alone when their T helper balance shifts toward to type 1.
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PMID:Clinical implications of the type 1/type 2 balance of helper T cells and P-glycoprotein function in peripheral T lymphocytes of myasthenia gravis patients. 1986 46