Richman R, Dobbins C, Voina S, Underwood L, Mahaffee D, Van Wyk J, Ney R L
J Clin Invest. 1973 Aug;52(8):2007-15. doi: 10.1172/JCI107385.
Adrenal ornithine decarboxylase activity was stimulated in a dose-related manner after administration of ACTH or dibutyryl ((6)N-2'-O-dibutyryl) cyclic AMP to hypophysectomized rats. Little effect was observed for 2 h, but striking increases in enzyme activity were observed 4 h after administration of these substances. Effects of ACTH and dibutyryl cyclic AMP were not secondary to stimulation of steroidogenesis, since hydrocortisone had no effect on adrenal ornithine decarboxylase although it did stimulate activity of the enzyme in the liver and kidney.ACTH, given subcutaneously to hypophysectomized rats, induced striking increases in adrenal cyclic AMP levels within 15-30 min with a fall towards the base line in 1 h. Increases in ornithine decarboxylase activity lag several hours after this endogenous cyclic AMP peak, in contrast to the stimulatin of steroidogenesis by the nucleotide that requires only 2-3 min. After graded doses of ACTH, increases in adrenal cyclic AMP levels at 30 min were paralleled by proportional increases in adrenal ornithine decarboxylase activity 4 h after hormone treatment. Whereas maximal levels of adrenal steroidogenesis have been observed at tissue cyclic AMP levels of 6 nmol/g. ACTH is capable of inducing increases in nucleotide levels up to 200 nmol/g or more. These high tissue levels of cyclic AMP, although unneccessary for maximal steroidogenesis, appear to stimulate adrenal ornithine decarboxylase activity. Several results in addition to the time lag in the stimulation of ornithine decarboxylase activity suggest a mechanism involving accumulation of the enzyme or some factor needed for its activity rather than direct activation of the enzyme by cyclic AMP. Thus, the addition of cyclic AMP directly to the ornithine decarboxylase assay mixture in vitro was without stimulatory effect. In addition, actinomycin D or cycloheximide in doses sufficient to block adrenal RNA and protein synthesis, respectively inhibited the stimulation of ornithine decarboxylase activity by ACTH in vivo. An adrenocortical cancer was found to maintain ornithine decarboxylase activity at very high levels, but did so at much lower cyclic AMP levels than those of ACTH-stimulated adrenals. It is concluded that ACTH stimulates adrenal ornithine decarboxylase activity and that this effect may be mediated by cyclic AMP. However, cyclic AMP be mediated by appear to be a determinant of the high level of enzyme activity found in adrenocortical cancer.
对垂体切除的大鼠给予促肾上腺皮质激素（ACTH）或二丁酰（（6）N - 2'-O - 二丁酰）环磷腺苷（dibutyryl cyclic AMP）后，肾上腺鸟氨酸脱羧酶活性呈剂量相关方式被刺激。给药后2小时几乎未观察到影响，但给药4小时后酶活性显著增加。ACTH和二丁酰环磷腺苷的作用并非继发于对类固醇生成的刺激，因为氢化可的松对肾上腺鸟氨酸脱羧酶没有影响，尽管它确实刺激了肝脏和肾脏中该酶的活性。
对垂体切除的大鼠皮下注射ACTH，在15 - 30分钟内肾上腺环磷腺苷水平显著升高，1小时后降至基线。鸟氨酸脱羧酶活性的增加在这种内源性环磷腺苷峰值出现数小时后才出现，这与核苷酸对类固醇生成的刺激仅需2 - 3分钟形成对比。给予不同剂量的ACTH后，30分钟时肾上腺环磷腺苷水平的升高与激素处理4小时后肾上腺鸟氨酸脱羧酶活性的成比例增加平行。虽然在组织环磷腺苷水平为6 nmol/g时已观察到肾上腺类固醇生成的最大水平，但ACTH能够使核苷酸水平升高至200 nmol/g或更高。这些高组织水平的环磷腺苷，尽管对于最大程度的类固醇生成并非必需，但似乎刺激了肾上腺鸟氨酸脱羧酶活性。除了鸟氨酸脱羧酶活性刺激存在时间滞后外，还有几个结果表明其机制涉及该酶或其活性所需的某些因子的积累，而非环磷腺苷对该酶的直接激活。因此，在体外将环磷腺苷直接添加到鸟氨酸脱羧酶测定混合物中没有刺激作用。此外，足以分别阻断肾上腺RNA和蛋白质合成的放线菌素D或环己酰亚胺在体内抑制了ACTH对鸟氨酸脱羧酶活性的刺激。发现肾上腺皮质癌将鸟氨酸脱羧酶活性维持在非常高的水平，但此时的环磷腺苷水平远低于ACTH刺激的肾上腺。结论是ACTH刺激肾上腺鸟氨酸脱羧酶活性，且这种作用可能由环磷腺苷介导。然而，环磷腺苷似乎并不是肾上腺皮质癌中发现的高水平酶活性的决定因素。
