The effects of the licorice derivative, glycyrrhetinic acid, on hepatic 3α- and 3β-hydroxysteroid dehydrogenases and 5α- and 5β-reductase pathways of metabolism of aldosterone in male rats

Abstract

Ingestion of licorice or treatment with chemical derivatives of glycyrrhetinic acid (GA), an active principle of licorice, can cause hypertension, sodium retention, and hypokalemia. Although GA has been shown to inhibit 11β-hydroxy steroid dehydrogenase, it may not be the only hepatic enzyme affected by this licorice derivative. Therefore, we studied the effects of GA on other major hepatic steroid-metabolizing enzymes from adrenalectomized male rats using aldosterone as the substrate; namely, Δ 4-5α and Δ 4-5β-reductases and 3α- and 3β-hydroxysteroid dehydrogenases (3α- and 3β-HSD). From these in vitro studies, we demonstrated that GA does not affect either microsomal 5α-reductase or cytosolic 3α-HSD activity. However, GA is a potent inhibitor of cytosolic 5β-reductase: the K(inis) and k(inii) were calculated from enzyme kinetic analysis to be 6.79 and 5.41 μm, respectively, using the Cleland equation, indicating that GA is a noncompetitive inhibitor of aldosterone. In addition, GA specifically inhibited microsomal 3β-HSD enzyme activity by what appears to be a competitive inhibition mechanism, causing a build-up of the intermediate, 5α-dihydroaldosterone (DHAldo). Thus, this study has indicated that GA has a profound effect on hepatic ring A-reduction of aldosterone. Inhibition of 5β-reductase and 3β-HSD results in decreased synthesis of both 3α, 5β-tetrahy-droaldosterone (THAldo) and 3β, 5α-THAldo and, hence, accumulation of aldosterone and 5α-DHAldo, both potent mineralocorticoids. Thus, more than one enzyme may be involved in the mechanism by which GA causes steroids, such as the glucocorticoid hormones, to display mineralocorticoid-like actions in humans and experimental animals. (Steroids 55:52–58, 1990)