Yamakita N, Chiou S, Gomez-Sanchez C E
Department of Internal Medicine, University of South Florida Health Sciences Center, Tampa.
Endocrinology. 1991 Nov;129(5):2361-6. doi: 10.1210/endo-129-5-2361.
The inhibiting effects of 18-ethynyl-deoxycorticosterone (18-E-DOC) as a mechanism-based inhibitor on the late steps of aldosterone biosynthetic pathway were examined in calf adrenal zona glomerulosa cells placed in the primary culture. Baseline and ACTH (10(-9) M)-, angiotensin-II (10(-8) M)-, and potassium (12 mM)-stimulated production of aldosterone and 18-hydroxycorticosterone were inhibited in a dose- and time-dependent manner. At 1 microM, 18-E-DOC produced a 73% inhibition, and at 10 microM, it produced a 94.6% inhibition of aldosterone secretion. Preincubation with 10 microM 18-E-DOC for 5 min followed by washing resulted in 75% inhibition of aldosterone secretion. The maximal degree of inhibition was reached after 60 min of preincubation. The degree of the inhibition of 18-hydroxycorticosterone production was almost same as that of aldosterone. Preincubation with 10 microM 18-E-DOC for 60 min, followed by extensive washing and reincubation with medium for 24 h, resulted in recovery to more than half the production of the control cells. Minimal changes occurred in the production of corticosterone (slight increase), 18-hydroxydeoxycorticosterone (slight increase) in zona glomerulosa cells, and cortisol (no changes) in zona fasciculata cells. These studies show that 18-E-DOC is a specific inhibitor of the late pathway of aldosterone biosynthesis. 18-E-DOC could be valuable as a therapeutic agent in those conditions associated with increased aldosterone production where a specific inhibitor would be useful.
在原代培养的小牛肾上腺球状带细胞中，研究了作为基于机制的抑制剂的18-乙炔基-脱氧皮质酮（18-E-DOC）对醛固酮生物合成途径后期步骤的抑制作用。醛固酮和18-羟皮质酮的基础分泌以及促肾上腺皮质激素（10⁻⁹ M）、血管紧张素II（10⁻⁸ M）和钾（12 mM）刺激后的分泌均受到剂量和时间依赖性抑制。在1 μM时，18-E-DOC产生73%的抑制作用，在10 μM时，它对醛固酮分泌产生94.6%的抑制作用。用10 μM 18-E-DOC预孵育5分钟后洗涤，导致醛固酮分泌受到75%的抑制。预孵育60分钟后达到最大抑制程度。18-羟皮质酮产生的抑制程度与醛固酮几乎相同。用10 μM 18-E-DOC预孵育60分钟，然后大量洗涤并在培养基中再孵育24小时，导致恢复到对照细胞产量的一半以上。球状带细胞中皮质酮（略有增加）、18-羟脱氧皮质酮（略有增加）的产生以及束状带细胞中皮质醇（无变化）的产生发生的变化最小。这些研究表明，(18-E-DOC)是醛固酮生物合成后期途径的特异性抑制剂。在那些醛固酮产生增加且特异性抑制剂有用的情况下，18-E-DOC作为治疗剂可能具有价值。
