Effects of glycyrrhetinic acid derivatives on hepatic and renal 11beta-hydroxysteroid dehydrogenase activities in rats

The purpose of this study was to examine the structure and activity relationships of glycyrrhetinic acid derivatives on the inhibition of hepatic and renal 11beta-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the...

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Published in:Journal of pharmacy and pharmacology 2003-06, Vol.55 (6), p.811-817
Main Authors: Shimoyama, Yoshihito, Hirabayashi, Kazuhiro, Matsumoto, Hiroatsu, Sato, Toshitsugu, Shibata, Shoji, Inoue, Hideo
Format: Article
Language:English
Subjects:
11-beta-Hydroxysteroid Dehydrogenases
Administration, Topical
Animals
Anti-Inflammatory Agents - pharmacology
Glycyrrhetinic Acid - analogs & derivatives
Glycyrrhetinic Acid - pharmacology
Hydroxysteroid Dehydrogenases - antagonists & inhibitors
Hydroxysteroid Dehydrogenases - metabolism
Kidney - drug effects
Kidney - enzymology
Liver - drug effects
Liver - enzymology
Male
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
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Summary:The purpose of this study was to examine the structure and activity relationships of glycyrrhetinic acid derivatives on the inhibition of hepatic and renal 11beta-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the inhibition of 11beta-HSD activity. 18beta-Glycyrrhetinic acid (Ia) potently inhibited 11beta-HSD activity of hepatic (IC50 (concentration giving 50% inhibition of cortisone production) = 0.09 microM) and renal (IC50 = 0.36 microM) homogenate. The inhibitory effect of 18beta-glycyrrhetol (Id) modified at the 30-position of glycyrrhetinic acid was weaker than that of glycyrrhetinic acid itself. 18beta-24-Hydroxyglycyrrhetinic acid (Ie), oxidized at the 24-position, remarkably reduced the inhibitory activity for both enzymes. 18beta-11-Deoxoglycyrrhetinic acid (IIc) showed the same inhibitory effect as glycyrrhetinic acid on hepatic 11beta-HSD activity, but less effect on renal 11beta-HSD activity. Furthermore, the inhibitory activity of 18beta-deoxoglycyrrhetol (IIa), modified at the 11- and 30-position, was markedly decreased. Dihemiphthalate derivatives (IIb, IIIb and IVb) of deoxoglycyrrhetol (IIa), 18beta-olean-9(11), 12-diene-3beta, 30-diol (IIIa) and olean-11, 13(18)-diene-3beta, 30-diol (IVa), which are anti-inflammatory agents, also showed weak inhibition against both hepatic and renal 11beta-HSDs. While glycyrrhetinic acid (200 mg kg(-1), p.o.) significantly inhibited 11beta-HSD activity in rat liver and kidney at 3 h after administration, compound IVb (100 mg kg(-1), p.o.) had no effect on either enzyme activity. In addition, the circulating corticosterone level was slightly increased by glycyrrhetinic acid but not by compound IVb. These results suggest that the anti-inflammatory effects of compound IVb, derived from glycyrrhetinic acid, are not due to accumulation of steroids induced by the inhibition of 11beta-HSD activity. Our data also showed that the 11-, 24- and 30-positions of glycyrrhetinic acid may play important roles in the differential inhibitory effects on 11beta-HSD isozyme activity.
ISSN:0022-3573