Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies.
In humans, glycyrrhetinic acid (GE), the active pharmacological ingredient of licorice, produces symptoms resembling those caused by excess mineralocorticoid secretion. We are proposing that 11 beta-dehydrogenase inhibition, and not intrinsic mineralocorticoid activity, is the primary mechanism of licorice induced pseudoaldosteronism. Glycyrrhizic acid (glycyrrhetinic acid glucuronide), when given orally to rats, partially inhibited renal 11 beta-dehydrogenase. In rats treated with dexamethasone before glycyrrhizic acid administration there was similar enzyme inhibition, suggesting that antimineralocorticoid effects of dexamethasone in licorice excess states are not mediated through a direct effect on 11 beta-dehydrogenase activity. Dispersed renal proximal tubular preparations, kidney homogenates, and microsomes readily converted corticosterone to 11-dehydrocorticosterone. GE and its synthetic analog carbenoxolone inhibited the conversion in these systems in a dose-dependent manner. Corticosteroid 11-oxoreductase, which was present in kidney homogenates at a level 10-20% that of 11 beta-dehydrogenase was not inhibited by any of the agents. With homogenate and microsomes, the Ki of GE was about 10(-9)-10(-8) M; with intact tubules, the Ki of GE was about 10(-5)-10(-6) M. It is suggested that a permeability barrier slows the entry of GE into the tubule cells. We conclude that the effects of licorice on corticosteroid metabolism in the kidney are based on its inhibition of 11 beta-dehydrogenase. Our data, supplemented by published evidence, is inconsistent with the conclusion that interaction with mineralocorticoid receptors accounts for the pharmacological effects of GE.
Monder
C
C
Population Council, Center for Biomedical Research, New York, New York 10021.
Stewart
P M
PM
Lakshmi
V
V
Valentino
R
R
Burt
D
D
Edwards
C R
CR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D019695:Glycyrrhizic Acid; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D011092:Polyethylene Glycols; D019695:Glycyrrhizic Acid; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D006034:Glycyrrhetinic Acid