INHIBITORY EFFECTS OF GLYCYRRHETIC ACID-DERIVATIVES ON 11-BETA-HYDROXYSTEROID AND 3-ALPHA-HYDROXYSTEROID DEHYDROGENASES OF RAT-LIVER

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