Mineralocorticoid effector mechanism of liquorice derivatives in human mononuclear leukocytes

Abstract

The mineralocorticoid effector mechanism of glycyrrhetinic acid and of its ester derivative carbenoxolone was evaluated in human mononuclear leukocytes by radioreceptorassay and measurement of intracellular sodium and potassium after incubation of the cells with or without the drugs. The affinity of both compounds for mineralocorticoid receptors in this human model was also compared with that found in kidney cytosol from adrenalectomized rats. Glycyrrhetinic acid possesses a measurable affinity for mineralocorticoid receptors in mononuclear leukocytes, which is 1:3,000 that of aldosterone itself. Carbenoxolone does not bind to the receptors in mononuclear leukocytes, in contrast with kidney cytosol where the drugs show a parallel affinity. The mean intracellular content of sodium in mononuclear leukocytes from 7 volunteers was 35% higher (p < 0.05) after incubation with 3 μmol glycyrrhetinic acid than after incubation with an equivalent amount of carbenoxolone, or in medium alone. The effect of glycyrrhetinic acid was completely reversed by addition of canrenone for the period of incubation. We conclude that the syndrome of pseudohyperal-dosteronism from carbenoxolone is thus probably not related to a direct agonist effect of the drug at the level of mineralocorticoid receptors, but that any action must follow in vivo conversion into glycyrrhetinic acid by hydrolysis.