Effect of Glabridin on Ion Transport Across Primary Human Bronchial Epithelial Cells

Glycyrrhiza glabra is one of 30 species of licorice which has been prescribed for centuries for a wide range of ailments and conditions. In particular, licorice root extract, as well as its main isoflavonoid constituent, glabridin, have been used to treat a variety of respiratory diseases, ranging from infection to asthma. As glabridin has been shown to modulate the activity of ion channels in other tissues, we determined the effect of glabridin on K⁺ and Cl⁻ secretion across primary human bronchial epithelial cells (HBEs), as these may represent therapeutic targets. Glabridin stimulated BK_Ca-dependent transepithelial potassium secretion across HBEs. In contrast, the glabridin derivative, vutiglabridin failed to stimulate K⁺ secretion and inhibited the glabridin-dependent K⁺ secretory current. Whole-cell patch-clamp studies on HEK cells expressing BK_Ca demonstrate that glabridin activates, whereas vutiglabridin inhibits, BK_Ca. We further demonstrate glabridin inhibits forskolin-mediated transepithelial Cl⁻ secretion across HBEs, while vutiglabridin has little effect. Using Fisher Rat Thyroid (FRT) cells stably expressing either wild type (FRT-WT) or F508del CFTR (FRT-F508del), we demonstrate glabridin neither potentiates WT CFTR nor corrects F508del CFTR. In contrast, whole-cell patch-clamp studies demonstrate glabridin inhibits KCa3.1 stably expressed in HEK cells. We previously demonstrated a role for KCa3.1 in forskolin-mediated Cl⁻ secretion across HBEs, likely explaining the inhibition of Cl⁻ secretion observed. In summary, we show that glabridin both stimulates BK_Ca-dependent K⁺ secretion and inhibits cAMP-mediated Cl⁻ secretion across HBEs. These findings support a role for BK_Ca in the therapeutic effects of glabridin in airway.