Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action

Abstract

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) is responsible for the interconversion of cortisol to cortisone [corticosterone (B) to 11-dehydrocorticosterone in rodents] and confers ligand specificity to the mineralocorticoid receptor. Inhibition of 11 beta HSD by licorice derivatives [glycyrrhizic and glycyrrhetinic (GE) acids] results in cortisol/B and not aldosterone acting as a potent mineralocorticoid. 11 beta HSD is ubiquitously expressed and, by converting active glucocorticoid to inactive metabolites, may be an important prereceptor regulator of ligand access to the glucocorticoid receptor (GR). To investigate this further, we have studied the effect of 11 beta HSD inhibition by licorice derivatives on PRL gene expression (a known glucocorticoid target gene) in rat pituitary GH3 cells. Glycyrrhizic acid administration to rats in vivo (75 mg/kg.day for 5 days) resulted in inhibition of 11 beta HSD activity, as previously reported, but also a significant reduction in steady state 11 beta HSD mRNA levels in both predominantly mineralocorticoid (kidney and distal colon) and glucocorticoid (liver and pituitary) target tissues. In vitro, 11 beta HSD mRNA and activity were present in rat pituitary GH3 cells (81% conversion of B to 11-dehydrocorticosterone/4 x 10(6) cells after 24-h incubation) and inhibited by GE in a dose-dependent fashion. While B or GE alone (10(-8)-10(-5) M) had little or no effect on PRL mRNA levels or immunoassayable PRL, combinations of GE plus B resulted in marked inhibition of PRL mRNA levels and secretion, to such an extent that a concentration of 10(-6) M B with 10(-6) M GE was more potent than equimolar concentration of the synthetic GR agonist RU 28362. This inhibitory effect on PRL mRNA levels was blocked by a 10-fold excess of the GR antagonist RU 38486, but not by a 10-fold excess of the mineralocorticoid receptor antagonist RU 26752, confirming that this potentiation of glucocorticoid hormone action was operating through the GR and not the mineralocorticoid receptor. In addition to its established role as a competitive inhibitor of 11 beta HSD, licorice results in pretranslational inhibition of 11 beta HSD both in vitro and in vivo. 11 beta HSD is clearly an important mechanism in regulating tissue levels of active glucocorticoid and, hence, ligand supply to the GR.