Effects of glycyrrhetinic acid derivatives on hepatic and renal 11β‐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 11β-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the inhibition of 11β-HSD activity. 18β-Glycyrrhetinic acid (Ia) potently inhibited 11β-HSD activity of hepatic (IC50 (concentration giving 50% inhibition of cortisone production) = 0.09 μm) and renal (IC50 = 0.36 μm) homogenate. The inhibitory effect of 18β-glycyrrhetol (Id) modified at the 30-position of glycyrrhetinic acid was weaker than that of glycyrrhetinic acid itself. 18β-24-Hydroxyglycyrrhetinic acid (Ie), oxidized at the 24-position, remarkably reduced the inhibitory activity for both enzymes. 18β-11-Deoxoglycyrrhetinic acid (IIc) showed the same inhibitory effect as glycyrrhetinic acid on hepatic 11β-HSD activity, but less effect on renal 11β-HSD activity. Furthermore, the inhibitory activity of 18β-deoxoglycyrrhetol (IIa), modified at the 11- and 30-position, was markedly decreased. Dihemiphthalate derivatives (IIb, IIIb and IVb) of deoxoglycyrrhetol (IIa), 18β-olean-9(11), 12-diene-3β, 30-diol (IIIa) and olean-11, 13(18)-diene-3β, 30-diol (IVa), which are anti-inflammatory agents, also showed weak inhibition against both hepatic and renal 11β-HSDs. While glycyrrhetinic acid (200 mg kg−1, p.o.) significantly inhibited 11β-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 11β-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 11β-HSD isozyme activity.