P-glycoprotein inhibition promotes prednisone retention in human sinonasal polyp explants.

BACKGROUND

P-glycoprotein (P-gp) is an efflux pump, which is part of the innate chemo-immunity defense system and is overexpressed in chronic rhinosinusitis with nasal polyps (CRSwNP). P-gp is capable of regulating corticosteroid retention and thus P-gp upregulation has been implicated in steroid resistance in several inflammatory disorders. The goal of this study is to determine whether P-gp regulates intracellular steroid retention in CRSwNP.

METHODS

This was a Massachusetts Eye and Ear Infirmary Institutional Review Board (IRB)-approved study in nasal polyp explants. Polyps were exposed to 50 μg/mL of prednisone for 30 minutes with or without the presence of a P-gp inhibitor (Verapamil 12.5 μM or Zosuquidar 0.31 μM) followed by a 40-minute washout period (n = 16 per group). Intracellular steroid retention was determined by quantifying the concentration of both intracytoplasmic and secreted steroid using an enzyme-linked immunosorbent assay (ELISA). Concentrations relative to control were compared using a Student t test.

RESULTS

The intracytoplasmic prednisone concentration was significantly greater relative to control following P-gp inhibition with Verapamil (155.28% ± 22.48%, p < 0.05) and Zosuquidar (125.81% ± 12.41%, p < 0.05). Similarly, the amount of prednisone secreted by the explant was significantly reduced at 30 minutes following P-gp inhibition with Zosuquidar (78.64% ± 2.98%, p < 0.05) and 40 minutes following P-gp inhibition with Verapamil (80.56% ± 5.02%, p < 0.05).

CONCLUSION

Inhibition of P-gp enhances the intracellular accumulation of prednisone in nasal polyps. This suggests that P-gp participates in regulation of glucocorticoid retention in sinonasal mucosa. These findings, coupled with the known overexpression of P-gp in CRSwNP, may point to a possible mechanism for steroid resistance in this patient population.