[The inhibitory effects of glycyrrhizin and glycyrrhetinic acid on the metabolism of cortisol and prednisolone--in vivo and in vitro studies].
This experiment was carried out to investigate the inhibitory effects of glycyrrhizin and its aglycon, glycyrrhetinic acid, on the metabolism of cortisol and prednisolone in vivo and in vitro. The effects of glycyrrhetinic acid on the metabolism of cortisol were examined in vitro using rat and bovine liver homogenate. Glycyrrhetinic acid inhibits both hepatic delta 4-5-reductase and 11 beta-hydroxysteroid dehydrogenase in a dose-dependent manner, resulting in the decrease of conversion of cortisol to cortisone, dihydrocortisol and tetrahydrocortisol in rats. The concentrations of glycyrrhetinic acid inducing 50% inhibition of rat liver delta 4-5-reductase and 11 beta-hydroxysteroid dehydrogenase were 2.5 x 10(-6) M and 8.5 x 10(-6) M, respectively. Glycyrrhetinic acid also inhibits bovine liver 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase in a dose-dependent manner, resulting in the decrease of conversion of cortisol to dihydrocortisol and prednisolone to 20-dihydroprednisolone. The concentrations of this drug inducing 50% inhibition of 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase were 8.2 x 10(-6) M and 6.5 x 10(-6) M, respectively. This is the first report which demonstrates the marked inhibitory effects of glycyrrhetinic acid on 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase in vitro. The effects of glycyrrhizin on the rate of metabolism of cortisol as well as prednisolone were studied in 23 patients with or without adrenal insufficiency. Glycyrrhizin had no effect on diurnal rhythm of plasma cortisol in 7 control subjects with normal pituitary adrenal axis, whereas glycyrrhizin significantly increased the half-time (T 1/2) and area under the curve (AUC) for plasma cortisol in 4 patients with adrenocortical insufficiency taking oral cortisol. Glycyrrhizin also increased T 1/2 and AUC for plasma prednisolone in 12 patients taking an oral prednisolone for at least 3 months. These results indicate that the suppression of hepatic delta 4-5-reductase, 11 beta-hydroxysteroid dehydrogenase and 20-hydroxysteroid dehydrogenase by glycyrrhizin and glycyrrhetinic acid may delay the clearance of cortisol and prednisolone and prolong the biological half-life of cortisol or prednisolone.
Ojima
M
M
Third Department Internal Medicine, Fukushima Medical College, Japan.
Satoh
K
K
Gomibuchi
T
T
Itoh
N
N
Kin
S
S
Fukuchi
S
S
Miyachi
Y
Y
D042842:11-beta-Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000328:Adult; D000368:Aged; D000818:Animals; D002417:Cattle; D004347:Drug Interactions; D005260:Female; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019695:Glycyrrhizic Acid; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000493:pharmacokinetics; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011239:Prednisolone / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
D019695:Glycyrrhizic Acid; D011239:Prednisolone; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D015089:20-Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; C021936:3-oxo-5 beta-steroid delta 4-dehydrogenase; D006034:Glycyrrhetinic Acid; D006854:Hydrocortisone