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Decreased activity of the multidrug resistance P-glycoprotein in acquired aplastic anaemia: possible pathophysiologic
R T Calado1, A B Garcia, R P Falcão
1Department of Clinical Medicine, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil.
Abstract:
To address a possible impairment of multidrug resistance mechanisms in acquired aplastic anaemia (AA), the functions of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) were respectively assessed by rhodamine 123 (Rh123) and daunorubicin (DNR) efflux in peripheral blood lymphocytes from AA patients. The proportion of Rh123-effluxing T cells was significantly decreased in AA, relative to controls. Interestingly, these changes were also present in patients with AA in remission. Conversely, Rh123 efflux in B and natural killer (NK) cells and DNR efflux in peripheral blood lymphocytes were unchanged. These data indicated that P-gp activity was decreased in AA not only during the development of the disease, but also after remission, introducing a new concept on the pathophysiology of AA by suggesting that it may contribute to drug-induced injury to haemopoietic cells in some cases of AA, by increasing the proportion of susceptible cells.
Insights
Multidrug resistance mechanisms, specifically P-glycoprotein function, are impaired in aplastic anemia (AA) patients, even in remission. This reduced P-glycoprotein activity may increase susceptibility to drug-induced injury in hematopoietic cells.
Area of Science:
- Hematology
- Cellular Biology
- Pharmacology
Background:
- Acquired aplastic anemia (AA) involves potential impairments in multidrug resistance (MDR) mechanisms.
- Understanding MDR function is crucial for comprehending AA pathophysiology and treatment responses.
Purpose of the Study:
- To investigate the function of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) in lymphocytes of AA patients.
- To determine if MDR mechanisms are altered in AA, even after disease remission.
Main Methods:
- Assessed P-gp function using rhodamine 123 (Rh123) efflux in T cells, B cells, and NK cells.
- Evaluated MRP function via daunorubicin (DNR) efflux in peripheral blood lymphocytes.
- Compared efflux activity between AA patients and healthy controls.
Main Results:
- A significant decrease in Rh123 efflux was observed in T cells from AA patients compared to controls.
- This reduced P-gp activity in T cells persisted even in patients with AA in remission.
- Rh123 efflux in B and NK cells, and DNR efflux in lymphocytes, remained unchanged.
Conclusions:
- P-glycoprotein activity is decreased in T cells of aplastic anemia patients, both during active disease and remission.
- Impaired P-gp function may contribute to the pathophysiology of AA by increasing hematopoietic cell susceptibility to drug-induced injury.