Adrenocortical steroids, preparations

Topical preparations Vehicles for presenting drugs to the skin Emollients, barrier preparations and dusting powders Topical analgesics Antipruritics Adrenocortical steroids Sunscreens... 

Preparations of Adrenocortical Steroids and Their Synthetic Analogs... 

Narasimhulu et ah (19) and Cooper et al. (7) observed that the addition of 17-hydroxyprogesterone to adrenocortical microsome preparations in the absence of TPNH produced a change in the difference spectrum characterized by the formation of an absorption minimum at 420 m/x and the simultaneous appearance of an absorption maximum at 390 m/x. Supplementation of the system with TPNH resulted in a gradual disappearance of the spectral change. Readdition of steroid substrate started a new cycle of appearance and disappearance of the spectral change. 

ACTH stimulates the synthesis of steroids by the cells of the adrenal cortex. The steroidogenic action of ACTH is mediated primarily by the intracellular messenger cyclic AMP acting via cyclic AMP-dependent protein kinase. The evidence for this is that (i) ACTH stimulates cyclic AMP production in intact adrenocortical cells and in plasma membrane preparations (ii) cyclic AMP analogues added to adrenocortical cells stimulate steroidogenesis to the same extent as ACTH and (iii) mutant adrenocortical cells with defective cyclic AMP-dependent protein kinase lack stimulation of steroidogenesis by ACTH [2],... 

Suitable derivatives to render most steroids more stable and volatile for gas chromatography and to improve their mass spectrometric properties have been developed. The trimethylsilyl ethers [206] or the methoxime-trimethylsilyl ethers of hydroxy keto steroids [207] have been widely used and their mass spectra extensively studied [204], A comparison of the GC-MS behaviour of several derivatives of some of the adrenocortical hormones has been made [208], including methoxime-trimethylsilyl ethers, dimethylsiliconides, methyl boronates, oxetanones and acetonides. The recently described improved preparation of enol-trimethylsilyl ethers of corticoids [209] should also prove of value. 

The fact that most of the Holarrhena alkaloids are characterized by substitution in position 18 was utilized for preparation of a series of nitrogen-free, 18-substituted steroids, which are of interest in relation to the adrenocortical hormone aldosterone. A detailed description would be beyond the scope of this summary. However, since some steps in these syntheses constitute interesting reactions of Holarrhena alkaloids, a brief outline, dealing with the principles of these procedures, will be presented here. 

Attempts to resolve the enzyme systems, which are tightly bound to mitochondrial or endoplasmic membranes, usually yield enzymatically inactive preparations. Only for the steroid ll)6-hydroxylase system of adrenocortical mitochondria has resolution into the following three components been accomplished (IS, 21, 22, 31) (1) a particulate fraction containing cytochrome P-450 (2) a fiavine-adeninedinucleotide fiavoprotein (MW 60,000) and (3) a non-heme iron protein (MW 20,000). The latter two constitute the TPNH-cytochrome P-450 reducing system. Full 11 -hy-... 

The apparent substrate dissociation constant Kg for cortexone of 4 X 10 M is quite similar to that of 17-hydroxyprogesterone in steroid 21-hydroxylase preparations from bovine adrenocortical microsomes (7). This distinguishes the adrenal steroid hydroxylases from the drug hydroxylases of rat liver where values of about lO M were observed (27). 

Cooper DY, Narasimhulu S, Slade A, Raich W, Forofif O, Rosenthal O (1965) Hemoprotein content and activity of solubilized steroid 11 beta-hydroxylase preparations from adrenocortical mitochondria. Life Sci 4 2109-2114... 

Cholesterol fatty acid esters (prepared enzymatically) do not appear to be cleaved to C21 steroids with hog adrenal homogenates under eonditions which yielded corticosteroids from cholesterol but under which no hydrolysis of the esters to cholesterol occur (Dailey et ah, 1962). Apparently cholesterol esters are hydrolyzed by dog adrenal homogenates (Dailey et al., 1963). Hydrolysis of cholesterol esters followed by degradation to isocaproic acid by bovine adrenocortical preparations has been observed by Raggatt and Whitehouse (1966). 

---