ADDITIONAL STUDIES ON THE MECHANISM OF ACTION OF ACTH

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Abstract
Additional studies are presented to support the concept that ACTH regulates the function of the adrenal cortex by activating adrenal glucose-6-phosphate dehydrogenase. Corticoid synthesis in a cell-free system of adrenal tissue, supplemented with glucose-6-phosphate, can be stimulated by synthetic 23 amino acid ACTH. ACTH is inactive if the lysine residues of the peptide chain are blocked. Estrogen competes with NADP+binding to glucose-6-phosphate dehydrogenase and inhibits the ACTH stimulus to steroidogenesis. Puromycin and other protein inhibitors have no effect on the initial activation of glucose-6-phosphate dehydrogenase and steroidogenesis. With longer incubation times puromycin can completely inhibit steroidogenesis, possibly by poisoning microsomal or mitochondrial elements. The initial event in the ACTH effect would seem to be the formation of an active complex of ACTH with glucose-6-phosphate dehydrogenase. This increases the rate of metabolism of glucose-6-phosphate and the rate of reduction of NADP+required for the hydroxylation reactions in corticoid synthesis. The increased activity of the pentose phosphate pathway with increased production of ribose sugars and ATP could increase DNA-directed RNA and protein synthesis as a secondary event.