P‐glycoprotein inhibition promotes prednisone retention in human sinonasal polyp explants

Abstract

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.