Effect of glabridin on ion transport across primary human bronchial epithelial cells.

Glycyrrhiza glabra is 1 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, has 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 BKCa-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 BKCa demonstrate that glabridin activates, whereas vutiglabridin inhibits, BKCa. We further demonstrate glabridin inhibits forskolin-mediated transepithelial Cl- secretion across HBEs, whereas 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 BKCa-dependent K+ secretion and inhibits cAMP-mediated Cl- secretion across HBEs. These findings support a role for BKCa in the therapeutic effects of glabridin in airway.NEW & NOTEWORTHY We demonstrate for the first time that the natural isoflavone, glabridin, stimulates transepithelial K+ secretion and inhibits forskolin-mediated Cl- secretion across primary human bronchial epithelial cells (HBEs). We demonstrate that these effects are due to the activation of BKCa and inhibition of KCa3.1, respectively. Furthermore, glabridin does not potentiate wild-type (WT) or correct F508del CFTR. In contrast, the glabridin derivative, vutiglabridin, inhibits BKCa and is antagonistic to the action of glabridin in HBEs.