Identity of the Site of Action of 3',5'-Adenosine Monophosphate and Adrenocortocotropic Hormone in Corticosteroidogenesis in Rat Adrenal and Beef Adrenal Cortex Slices^*

Abstract

In addition, neither 3',5'-AMP nor ACTH stimulated the transformation of [7a-3H]pregnenolone (3/3-hydroxy-5-pregnen-3-one) or [7-3H]progesterone (4-pregnene-3,20-dione) to corticosteroids. The results indicate that both 3',5'-AMP and ACTH stimulate at the same site in the biosynthetic pathway for corticosteroids, i.e., between cholesterol and pregnenolone, and suggest that 3 ',5 '-AMP is an obligatory intermediate in the action of ACTH.

Recent advances in the role of StAR

“…Since those early observations, many studies have indicated that the true rate limiting step effected by hormone stimulation is the delivery of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane and the P450scc enzyme (Karaboyas et al, 1965;Simpson et al, 1979;Crivello and Jefcoate, 1980;Privalle et al, 1983;Jefcoate et al, 1987). Diffusion of the hydrophobic cholesterol through the aqueous intermembrane space is extremely slow (Rennert et al, 1993) and, therefore, it became clear that the transfer of cholesterol from the outer membrane to the P450scc occurs in an assisted manner and that this is the rate limiting step.…”

The role of the StAR protein in steroidogenesis: challenges for the future

“…Regardless of tissue origin, however, a common feature of all steroid hormones is that their synthesis utilizes a common precursor, namely, cholesterol. In fact, it is the delivery of cholesterol to the site of its first enzymatic conversion that constitutes the rate-limiting and hormonally regulated step in steroidogenesis (Karaboyas & Koritz 1965, Brownie et al 1972, Simpson et al 1979, Crivello & Jefcoate 1980, Privalle et al 1983, Jefcoate et al 1987. In general terms, cellular cholesterol residing in the outer mitochondrial membrane, lipid droplets or plasma membranes of steroidogenic cells, must be delivered to the inner mitochondrial membrane, the site of the cytochrome P450 side chain cleavage enzyme (P450scc) which converts cholesterol to pregnenolone, the first steroid formed in all steroidogenic tissues.…”

A Study of the Mechanisms by Which Adrenocorticotropic Hormone Maintains Adrenal Steroidogenic Responsiveness*

“…There is considerable evidence that the rapid 1916 stimulation of steroid biosynthesis following an acute injection of ACTH is primarily the result of an increased rate of conversion of cholesterol to A5-pregnenolone (4,5). The A5-pregnenolone thus formed is converted in sequence to progesterone, deoxycorticosterone, and corticosterone by the rat adrenal, a process that is not influenced to a major degree by ACTH over short time intervals (5).…”

“…The A5-pregnenolone thus formed is converted in sequence to progesterone, deoxycorticosterone, and corticosterone by the rat adrenal, a process that is not influenced to a major degree by ACTH over short time intervals (5). The acute effect of ACTH can be blocked by a variety of inhibitors of protein synthesis (6)(7)(8).…”

“…One of these inhibitors, cycloheximide, has been shown to block the increased conversion of cholesterol to M5-pregnenolone which is brought about acutely by ACTH (9). The adrenal conversion of A5-pregnenolone to corticosterone, which is relatively insensitive to ACTH over short time intervals (5), is not inhibited by cycloheximide over similar time intervals (7). Since total adrenal protein synthesis does not measurably increase during the short period of ACTH administration required for the rapid stimulation of steroidogenesis (7), it has been postulated that this acute effect of ACTH involves synthesis of a relatively specific protein fraction that plays a role in the control of steroidogenesis.…”