Study of Effects of Glycyrrhetinic acid and its Derivatives on Δ<SUP>4</SUP>5α and 5β-Reductase by Rat Liver Preparations

Abstract

Mineralocorticoid-mimetic action of glycyrrhetinic acid (GA) or glycyrrhizin (GL) and its benefficial effect on some patients with Addison's disease were reported.Several authors noted that GA or GL was ineffective in patients with severe Addison's disease or in patients subjected to bilateral adrenalectomy, when used alone, but quite effective in maintaining a satisfactory clinical state, when used in conjunction with a subminimal dose of cortisol. Kumagai and Atherden found significant inhibition by GA or GL in steroids-Δ4-reduction in rat liver homogenate and a hypothesis was pro-posed that this synergistic action of GA, GL and cortisol might be attributed to the inhibitory effect of GA or GL on corticosteroid mtabolism in the liver.Livers contain two Δ4-recdutase systems, a soluble Δ4-5β-reductase and a microsomal-5α-reductase. In human beings, 5β-reductase is quantitatively the major enzyme and physiologicaly important in the regulation of cortisol and aldosterone metabolism.This experiment was carried out to investigate the pattern of inhibitory effects of GA and its derivatives on the metabolism of testosterone, aldosterone and cortisol by microsomal and soluble fractions obtained from male rat liver and to clarify its clinical significance.In vitro studies demonstrated that GA, GL and dioxo-GA (DGA) inhibited Δ4-5β-reduction to much greater extent than Δ4-5α-reduction of these three steroids. Especially GA showed the most profound inhibitory effect on Δ4-5β-reduction. On the other hand, GA, DGA and GL inhibited Δ4-5α-reduction to a very small extent.GA (0.2 mg, 4.0 mg, 50.0 mg/100 g B.W. for 7 days) and GL (0.5 mg, 5.0 mg, 50.0 mg/ 100 g B.W. for 14 days) were administered as daily intramuscular injection and their effects on Δ4-5α and 5β-reductase activity were investigated. The results showed that GA (0.4 mg and 50 mg administration) and GL (50 mg administration only) significantly lowered Δ4-5β-reducatse activity. But on the contrary Δ4-5α-reductase activity was markedly increased, when only 50 mg of GA and GL was administered. The mechanism of this increase of Δ4-5α-reductase activity remains to be clarified.According to Blair and Kitay, it is suggested that the liver possesses an autoregulatory mechanims for the control of plasma corticosteroids and changes in hepatic Δ4-reductase activity in vitro are closely paralleled by the biological half-life of corticosteroids in vivo.In man cleavage of the A-ring of aldosterone and cortisol depends overwhelmingly on Δ4-5β-reductase activity, ie. the ratio of 5β/5α is said to be 20 : 1 or more. Thus from the studies presented here, it can be presumed that the suppression of Δ4-5β-reductase activity by GA or GL administration may delay the clearance of corticosteroids and prolong the biological half-life of cortisol or aldosterone, resulting in the synergism of these steroids and GA or GL.