Background Several mechanisms of glucocorticoid resistance in asthma have been proposed. P-glycoprotein (P-gp), a ubiquitous efflux transport protein, is associated with variability in the disposition of many drugs and interindividual variability in drug treatment response. This study was undertaken to determine the effect of P-gp expression on glucocorticoid efflux from airway epithelial cells.
Hypothesis Decreasing respiratory epithelial P-gp expression in dexamethasone-exposed airway epithelial cells in vitro will increase intracellular dexamethasone concentration.
Methods A549 lung epithelial cells, transfected with small interfering RNA (siRNA) targeted at messenger RNA for the gene encoding P-gp, were exposed to 100-nM dexamethasone for 15 minutes. Transfection efficiency of siRNA, P-gp expression, and intracellular dexamethasone were measured with flow cytometry.
Results Cells transfected with both negative siRNA and siRNA targeted at P-gp exhibited a positive correlation of P-gp expression with intracellular dexamethasone. The mean ± SEM correlation coefficients were 0.78 ± 0.07 for cells transfected with negative siRNA and 0.79 ± 0.08 for cells transfected with siRNA targeted at P-gp.
Discussion Contrary to our hypothesis, the positive correlation between P-gp expression and intracellular dexamethasone suggests that P-gp is not a primary transporter of glucocorticoids from airway epithelial cells. Increased P-gp expression is unlikely to be an important mechanism of glucocorticoid resistance in asthma.
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