Ojima M, Satoh K, Gomibuchi T, Itoh N, Kin S, Fukuchi S, Miyachi Y
Third Department Internal Medicine, Fukushima Medical College, Japan.
Nihon Naibunpi Gakkai Zasshi. 1990 May 20;66(5):584-96. doi: 10.1507/endocrine1927.66.5_584.
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.
本实验旨在研究甘草酸及其苷元甘草次酸对皮质醇和泼尼松龙体内及体外代谢的抑制作用。使用大鼠和牛肝匀浆在体外研究了甘草次酸对皮质醇代谢的影响。甘草次酸以剂量依赖的方式抑制肝脏δ4-5-还原酶和11β-羟基类固醇脱氢酶，导致大鼠体内皮质醇向可的松、双氢皮质醇和四氢皮质醇的转化减少。诱导大鼠肝脏δ4-5-还原酶和11β-羟基类固醇脱氢酶50%抑制的甘草次酸浓度分别为2.5×10(-6)M和8.5×10(-6)M。甘草次酸还以剂量依赖的方式抑制牛肝11β-羟基类固醇脱氢酶和20-羟基类固醇脱氢酶，导致皮质醇向双氢皮质醇的转化以及泼尼松龙向20-二氢泼尼松龙的转化减少。诱导11β-羟基类固醇脱氢酶和20-羟基类固醇脱氢酶50%抑制的该药物浓度分别为8.2×10(-6)M和6.5×10(-6)M。这是首次报道证明甘草次酸在体外对11β-羟基类固醇脱氢酶和20-羟基类固醇脱氢酶有显著抑制作用。在23例有或无肾上腺功能不全的患者中研究了甘草酸对皮质醇以及泼尼松龙代谢速率的影响。甘草酸对垂体-肾上腺轴正常的7例对照受试者的血浆皮质醇昼夜节律无影响，而甘草酸显著增加了4例口服皮质醇的肾上腺皮质功能不全患者血浆皮质醇的半衰期（T 1/2）和曲线下面积（AUC）。甘草酸还增加了12例口服泼尼松龙至少3个月患者血浆泼尼松龙的T 1/2和AUC。这些结果表明，甘草酸和甘草次酸对肝脏δ4-5-还原酶、11β-羟基类固醇脱氢酶和20-羟基类固醇脱氢酶的抑制作用可能会延迟皮质醇和泼尼松龙的清除，并延长皮质醇或泼尼松龙的生物半衰期。
