Inhibitory Effects of Glycyrrhetic Acid Derivatives on 11β- and 3α-Hydroxysteroid Dehydrogenases of Rat Liver

Abstract

Glycyrrhetic acid (GA), an aglycone of glycyrrhizin (GL), is a potent inhibitor of 11β- and 3α-hydroxysteroid dehydrogenases. 11β-Hydroxysteroid dehydrogenase activity of rat liver microsomes was potently inhibited by GA, 3-deoxyglycyrrhetic acid (3-deoxy GA), 3-ketoglycyrrhetic acid (3-ketoGA), 3-epiglycyrrhetic acid (3-epiGA) and 11-deoxoglycyrrhetic acid (11-deoxoGA), with I₅₀ values of 2-4×10^-7M. However, 18α-stereoisomers (I₅₀=3-7×10^-6M) of GA, 3-deoxyGA and 11-deoxoGA were one tenth less inhibitory on the enzyme activity than the corresponding 18β-isomers. On the other hand, 18α-stereoisomers of GA, 3-deoxyGA and 11-deoxoGA inhibited 3α-hydroxy-steroid dehydrogenase activity of rat liver cytosol more potently than the corresponding 18β-isomers. I₅₀ values of 18α- and 18β-isomers were 2 and 7×10^-6M, respectively, in the case of GA, 8 and 20×10^-6M in 3-deoxyGA, 3 and 20×10^-6M in 11-deoxoGA. These results indicate that the 18β-conformation of oleanane is important for the inhibition of 11β-hydroxysteroid dehydrogenase but on the contrary the 18α-conformation is important for the inhibition of 3α-hydroxysteroid dehydrogenase.