グリチルレチン酸及びその誘導体のラット肝Δ<SUP>4</SUP>-3ketosteroids-5α及び5β-reductaseに対する影響について
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Mineralocorticoid-mimetic action of glycyrrhetinic acid (GA) or glycyrrhizin (GL) and its benefficial effect on some patients with Addison's disease were reported.<BR>Several authors noted that GA or GL was ineffective in patients with severe Addison's disease or in patients subjected to bilateral adrenalectomy, when used alone, but quite effective in maintaining a satisfactory clinical state, when used in conjunction with a subminimal dose of cortisol. Kumagai and Atherden found significant inhibition by GA or GL in steroids-Δ<SUP>4</SUP>-reduction in rat liver homogenate and a hypothesis was pro-posed that this synergistic action of GA, GL and cortisol might be attributed to the inhibitory effect of GA or GL on corticosteroid mtabolism in the liver.<BR>Livers contain two Δ<SUP>4</SUP>-recdutase systems, a soluble Δ<SUP>4</SUP>-5β-reductase and a microsomal-5α-reductase. In human beings, 5β-reductase is quantitatively the major enzyme and physiologicaly important in the regulation of cortisol and aldosterone metabolism.<BR>This experiment was carried out to investigate the pattern of inhibitory effects of GA and its derivatives on the metabolism of testosterone, aldosterone and cortisol by microsomal and soluble fractions obtained from male rat liver and to clarify its clinical significance.<BR>In vitro studies demonstrated that GA, GL and dioxo-GA (DGA) inhibited Δ<SUP>4</SUP>-5β-reduction to much greater extent than Δ<SUP>4</SUP>-5α-reduction of these three steroids. Especially GA showed the most profound inhibitory effect on Δ<SUP>4</SUP>-5β-reduction. On the other hand, GA, DGA and GL inhibited Δ<SUP>4</SUP>-5α-reduction to a very small extent.<BR>GA (0.2 mg, 4.0 mg, 50.0 mg/100 g B.W. for 7 days) and GL (0.5 mg, 5.0 mg, 50.0 mg/ 100 g B.W. for 14 days) were administered as daily intramuscular injection and their effects on Δ<SUP>4</SUP>-5α and 5β-reductase activity were investigated. The results showed that GA (0.4 mg and 50 mg administration) and GL (50 mg administration only) significantly lowered Δ<SUP>4</SUP>-5β-reducatse activity. But on the contrary Δ<SUP>4</SUP>-5α-reductase activity was markedly increased, when only 50 mg of GA and GL was administered. The mechanism of this increase of Δ<SUP>4</SUP>-5α-reductase activity remains to be clarified.<BR>According to Blair and Kitay, it is suggested that the liver possesses an autoregulatory mechanims for the control of plasma corticosteroids and changes in hepatic Δ<SUP>4</SUP>-reductase activity in vitro are closely paralleled by the biological half-life of corticosteroids in vivo.<BR>In man cleavage of the A-ring of aldosterone and cortisol depends overwhelmingly on Δ<SUP>4</SUP>-5β-reductase activity, ie. the ratio of 5β/5α is said to be 20 : 1 or more. Thus from the studies presented here, it can be presumed that the suppression of Δ<SUP>4</SUP>-5β-reductase activity by GA or GL administration may delay the clearance of corticosteroids and prolong the biological half-life of cortisol or aldosterone, resulting in the synergism of these steroids and GA or GL.
- 日本内分泌学会の論文
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