Adrenocorticotropic hormone biosynthesis

Haynes, R.C., and Murad, F. (1985). Adrenocorticotropic hormone adrenocortical steroids and their synthetic analogs inhibitors of adrenocortical steroid biosynthesis. In Goodman and Gilman s The Pharmacological Basis of Therapeutics (Goodman, A.G., Goodman, L.S., Rell, T.W. and Murad, F., Eds.). Macmillan, New York, pp. 1459-1489. 

Figure 16.11 Control of catecholamine biosynthesis in the adrenal medulla. TH, tyrosine hydroxylase DBH, dopamine hydroxylase PNMT, phenylethanolamine methyl-transferase ACTH, adrenocorticotropic hormone. The heavy arrows indicate major sites of regulation. (Reproduced by permission from Axelrod, J. Reisine TD. Stress hormones their interaction and regulation. Science 224 452-459, 1984.)...

Sachazkaja, T., Influence of adrenocorticotropic hormone on the biosynthesis of A -3-unsaturated steroids in the adrenals of human foetuses. Excerpta Med. Intern. Congr. Ser. Ill, 287-288 (1966). 

The final step in cortisol synthesis requires transport of 11-deoxycortisol back to the inner membrane of the mitochondria, where P450cn (11-P-hydroxylase) receives electrons from electron transport protein intermediates (adrenodoxin, which when oxidized is reduced by adrenodoxin reductase). The enzyme then transfers these reducing equivalents by way of oxygen to 11-deoxycortisol for hydroxylation at Cl 1 to form cortisol. The rate of biosynthesis of cortisol and other adrenal steroids is dependent on stimulation of the adrenal cortical cells by adrenocorticotropic hormone (ACTH). 

The drug is a purely synthetic compound which possesses a distinct unique characteristic feature of inhibiting 11 -P-hydroxylation in the biosynthesis of cortisol, corticosterone and aldosterone. Therefore, it is invariably employed to test for hypothalamic-pituitary function. However, in the normal individual, the drug essentially blocks the specific enzymatic step that ultimately leads to the synthesis of cortisol and corticosterone in vivo), causing an absolute intense stimulation of adrenocorticotropic hormone (ACTH) secretion and inducing thereby a marked and pronounced enhancement in the urinary excretion of 17-hydroxy-corticosteroids. 

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