11 beta-Hydroxysteroid dehydrogenase alleviates glucocorticoid-mediated inhibition of steroidogenesis in rat Leydig cells.
11 beta-Hydroxysteroid dehydrogenase alleviates glucocorticoid-mediated inhibition of steroidogenesis in rat Leydig cells.
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DOI：
10.1210/endo.134.3.8119160
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发表时间：
1994-03
期刊：
影响因子：
4.8
通讯作者：
C. Monder;Y. Miroff;A. Marandici;Matthew P. Hardy
中科院分区：
文献类型：
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作者：
C. Monder;Y. Miroff;A. Marandici;Matthew P. Hardy
来自成熟大鼠睾丸的Leydig细胞含有高水平的11 β-羟基类固醇脱氢酶（11 HSD），这是一种使糖皮质激素氧化失活的酶。我们已经提出Leydig细胞的11 HSD保护睾丸免受高水平糖皮质激素的影响，这可能发生在应激和库欣病中。在本文中，我们调查是否睾丸11 HSD失活糖皮质激素降低其抑制睾酮（T）的生产能力。皮质酮（B）和地塞米松（DEX）以剂量依赖的方式抑制纯化的Leydig细胞产生T。1.5 nM DEX与0.4 μ M B相比，活性降低50%。抑制曲线的形状与饱和过程一致;糖皮质激素受体拮抗剂RU 486克服了这两种类固醇的抑制作用。我们的结论是，这种作用是由糖皮质激素受体介导的。醛固酮、11 β-羟孕酮和11-脱氧皮质酮不降低T的产生。与B相比，DEX的更大效力可能是由于其对11 HSD氧化失活的抗性。由于11-脱氢皮质酮（11 HSD氧化B的产物）不抑制T的产生，因此预测11 HSD的失活应增强B的抑制作用。与这一预测一致，抑制B增加甘珀酸，11 HSD的抑制剂，变得更类似于DEX。DEX（不是11 HSD的底物）对T产生的抑制不受甘珀酸的影响。我们的结论是，通过减少抑制性糖皮质激素的水平，11 HSD有一个新的作用间质细胞类固醇代谢酶在调节T生产。
Leydig cells from mature rat testes contain high levels of 11 beta-hydroxysteroid dehydrogenase (11HSD), an enzyme that oxidatively inactivates glucocorticoids. We have proposed that the 11HSD of Leydig cells protects the testis from the effects of high levels of glucocorticoids, as may occur in stress and Cushing's disease. In this paper we investigate whether testicular 11HSD by inactivating glucocorticoids diminishes their ability to inhibit testosterone (T) production. Corticosterone (B) and dexamethasone (DEX) inhibited T production by purified Leydig cells in a dose-dependent manner. Activity was diminished by 50% with 1.5 nM DEX vs. 0.4 microM B. The shapes of the inhibition curves were consistent with a saturable process; inhibition by both steroids was overcome with the glucocorticoid receptor antagonist RU486. We concluded that the effect was mediated by glucocorticoid receptors. Aldosterone, 11 beta-hydroxyprogesterone, and 11-deoxycorticosterone did not decrease T production. The greater potency of DEX compared to B may be due to its resistance to oxidative inactivation by 11HSD. As 11-dehydrocorticosterone, the product of the oxidation of B by 11HSD, did not inhibit T production, it was predicted that inactivation of 11HSD should enhance the inhibitory effect of B. Consistent with this prediction, inhibition by B was increased by carbenoxolone, an inhibitor of 11HSD, becoming more similar to that by DEX. Suppression of T production by DEX (which is not a substrate of 11HSD) was unaffected by carbenoxolone. We conclude that through reduction of the levels of inhibitory glucocorticoids, 11HSD has a novel role among Leydig cell steroid-metabolizing enzymes in the regulation of T production.