Pathway for Cortisol Biosynthesis in the Foetal Adrenal Cortex

Abstract

HUMAN adrenal tissue, both normal and hyperplastic, or from patients with mammary carcinoma, has the capacity to convert both pregnenolone and progesterone to corticosteroids in vitro^1–3. There is often a clear distinction between the ways in which these substrates are used, however, in that pregnenolone is preferentially converted to the 17α-hydroxycorticoids, whereas progesterone seems to be more important as a substrate for 17-deoxycorticoid formation^2,3. The isolation of 17 α-hydroxypregnenolone in particularly high yields during the early stages of an incubation with radioactive pregnenolone strongly suggests the intermediary role of this compound³. Nevertheless, the nature of the biosynthetic pathway by which 17α-hydroxypregnenolone is transformed to cortisol is not clear. It is possible that this compound may be acted on by a Δ⁵,3β-hydroxysteroid dehydrogenase system to yield 17α-hydroxyprogesterone²; as an alternative, the work of Pasqualini, Lafoscade and Jayle⁴ suggests that further hydroxylation at C-21, to yield 17α,21-dihydroxypregnenolone, may precede the formation of Δ⁴,3-ketones. This pathway may also occur in the foetus⁵. In our earlier investigation³, a significant yield of 17α-hydroxyprogesterone was formed from pregnenolone, but no evidence was found for the production of further Δ⁵,3β-hydroxy compounds which could be intermediates in the biosynthesis of cortisol. In order to study this problem further, a kinetic study was undertaken of the products obtained from foetal human adrenal tissue incubated with [4–¹⁴C] 17α-hydroxyprogesterone and [7α–³H] 17α-hydroxypregnenolone.