title: Effects of glycyrrhetinic acid derivatives on hepatic and renal 11beta-hydroxysteroid dehydrogenase activities in rats.
abstract: 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.
authors.affiliation: Research Laboratory, Minophagen Pharmaceutical Co., Ltd, 2-2-3 Komatsubara, Zama-shi, Kanagawa 228-0002, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Shimoyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hirabayashi
authors.forename: Hiroatsu
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Toshitsugu
authors.initials: T
authors.lastname: Sato
authors.forename: Shoji
authors.initials: S
authors.lastname: Shibata
authors.forename: Hideo
authors.initials: H
authors.lastname: Inoue
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006034:Glycyrrhetinic Acid