Deoxycorticosterone synthesis

All these steroids disappear from the brain in animals after removal of the adrenals or gonads (ovary and testis). This also applies to tetrahydrodeoxycorticosterone for although it is formed by reduction of deoxycorticosterone within the brain, its synthesis depends on that steroid coming from the blood. 

The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and excretion of potassium. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system. 

Woodward s synthesis of steroids, described in Scheme 3.1, illustrates the value of a carefully thought out general plan for a synthesis. This synthesis targeted the preparation of the tetracyclic keto aldehyde 1, which can be used as an advanced intermediate to be converted into a set of natural steroids that includes progesterone 2, deoxycorticosterone 3, androsterone 4, testosterone 5, cholesterol 6, and cortisone 7 via well-known routes. The synthetic plan for 1 required solving the following key tasks ... 

Carboxymethyloxime formation is reported for a variety of 3-oxo- and 7-oxo-steroids, suitably protected at other oxo-groups (C-17 or C-20) where necessary. Syn- and anti-forms of carboxymethyloximes were separated by repeated t.l.c." The 6-carboxymethyloximino-derivative (479) of oestetrol was used as hapten in the production of a highly specific antiserum for oestetrol. " The synthesis of 6-oxo-oestetrol proceeded through known steps. RIA of 18-hydroxy-deoxycorticosterone (480) ° has been based upon the 3-carboxymethyloxime of the intact steroid, but 18-hydroxycorticosterone (481) was degraded by periodic acid to the y-lactone (482) before formation of its 3-carboxymethyloxime. The antiserum to this y-lactone responds equally to the y-lactone derived from 18-hydroxydeoxycorticosterone, but other corticosteroids did not interfere. 

A defect in the synthesis of aldosterone in infancy may not be permanent. Royer et al. (R18) reported two siblings with a salt-losing syndrome who responded well to 11-deoxycorticosterone acetate when one of the children was reinvestigated after 5 years, it was found that the aldosterone secretion rate was normal. Two infants studied by Russell and co-worker (R19) had salt loss in infancy and were treated with salt and 11-deoxycorticosterone acetate, but it was possible to discontinue the treatment of one infant at the age of 12 months and the other after SY2 years. 

The metyrapone test may be used diagnostically to evaluate the proper functioning of the anterior pituitary gland. When administered orally, metyrapone inhibits the activity of 11-beta-hydroxylase, which is necessary for the synthesis of cortisol, corticosterone, and aldosterone, promotes the release of corticotropin, which in turn increases production of the precursors (11-deoxycortisol and 11-deoxycorticosterone), and enhances the appearance of 17-hydroxycorticoster-oids and 17-ketogenic steroids. 

The glucocorticoids mainly influence carbohydrate metabolism and, to a certain extent, protein and lipid metabolism (see Table 14 and Figure 55). The main glucocorticoid is cortisol, with a daily secretion of 15 mg. Cortisol is synthesized through the 11-beta-hydroxylation of 11-deoxy-cortisol. Besides cortisol, the adrenal gland also synthesizes and releases a small amount of corticosterone, whose synthesis from 11-deoxycorticosterone is catalyzed by 11-beta-hydroxylase. A deficiency of 11-beta-hydroxylase causes ... 

Iodo 20-oxo steroids are important intermediates for synthesis of 21-hydroxy 20-oxo steroids, e.g., dehydrocorticosterone and cortisone,711 also deoxycorticosterone 712 so the preparation of these a>iodo ketones by the following very interesting reaction with iodine should be noted ... 

In the pathway of cortisol synthesis, the 17-hydroxylation of progesterone yields 17-a-hydroxyprogesterone, which, along with progesterone, is transported to the smooth endoplasmic reticulum. There the membrane-bound P450c2i (21-a-hydrox-ylase) enzyme catalyzes the hydroxylation of C21 of 17-a-hydroxyprogesterone to form 11-deoxycortisol (and of progesterone to form deoxycorticosterone [DOC], a precursor of the mineralocorticoid, aldosterone see Fig. 34.23). 

Pugsley, D.J., Mullins, R. and Beilin, L.J. (1976). Renal prostaglandin synthesis in hypertension induced by deoxycorticosterone and sodium chloride in the rat. Clin. Sci. Mol Med., 51, 253s-256s... 

Through the use of impure yeast cultures, Mamoli and Vercellone (M-538, M-540, M-542, M-552) discovered a useful class of sequential oxidation-isomerization reactions which they later attributed correctly to the action of the bacterial contaminants (M-553). A representative transformation of this type (including a hydrolysis step, as well) is the conversion of 3/3,21 -dihydroxy-5-pregnen-20-one 21-acetate to deoxycorticosterone by Corynebacterium mediolnnum (Corynebacterium helvolum) (M-541, M-546). Sobering (USA) employed a similar process to manufacture Reich-stein s Compound S (17fl , 21-dihydroxy-4-pregnene-3, 20-dione) for a time. It is now clear that nonenzymatic methods are more efficient for the synthesis of Compound S. 

Steroid Ilfi-Hydroxylase (EC 1.14.15.4). Decreased cortisol synthesis induces increased ACl H secretion with resulting overproduction of deoxycorticosterone (a potent salt-retaining hormone). Iririlization in both sexes and female pseudohermaphroditism. Not all patients show hypertension... 

P450 21A2 is the enzyme involved in the 21-hy-droxylation of progesterone and 17-hydroxy-progesterone, yielding deoxycorticosterone and 11-deoxycortisol from the two substrates, respectively (Fig. 9.12). The 21-hydroxylation reaction is an important step in the synthesis of glucocorticoids and mineralocorticoids, and de-... 

In such a case of 17-hydroxylase deficiency, the levels of these compounds in tissues and plasma are increased 10-40 times above normal. However, aldosterone production decreases in these patients, and this decrease is believed to result from secondary inhibition of aldosterone synthesis by other mineralocorti-coids, deoxycorticosterone and corticosterone. In any event, the disease is associated with hypogonadism and excess mineralocorticoid activity. 

In the acrenal, a hormone s effect on steroidogenesis concerns at least three steps in steroid metabolism (1) a protein synthesis-independent stimulation of the conversion of cholesterol ester to cholesterol (2) an actinomycin-, cycloheximide —, and puromycin-sensi-tive stimulation of the conversion of cholesterol to pregnenolone and (3) an activation of C-11 j8-hydrox-ylase, the enzyme that converts 11-deoxycorticosterone to corticosterone. 

Mitochondrial CYP11B2 (also known as CYPllp or steroid lip-hydroxylase) is involved in the synthesis of aldosterone. Aldosterone affects the conservation of sodium, the secretion of potassium, water retention, and blood pressure. CYPl 1B2 has been shown to catalyze the terminal regio- and stereospecific hydroxylation of deoxycorticosterone to aldosterone however, the exact mechanism of this process was not solved. Rapid-quenching experiments with the membrane-bound bovine CYP11B2 incorporated into liposome membranes have demonstrated that aldosterone is produced via corticosterone and not via 18-hydroxydeoxycorticosterone. Moreover, a kinetic analysis suggested a successive mechanism of aldosterone production from corticosterone, which did not dissociate from the binding site of the enzyme [34] (Scheme 5.5). 

Fig. 17). An alternate route to the adrenocortical steroids which does not require the intermediary of progesterone has been discussed by Hechter (1958). The synthesis of aldosterone requires an additional oxidation at Cl8- It is known that progesterone, deoxycorticosterone and corticosterone can all be converted to aldosterone under certain conditions, but no definite assignment of the sequence of nuclear oxidations is possible at the present time. 

The elimination of the side chain, which here leads to the synthesis of a hormone, is on the other hand a catabolic reaction for the adrenal cortical hormone 17-hydroxy-l 1-deoxycorticosterone. As we have mentioned, the hormones are inactivated by reduction in ring A. The urinary excretion product androsterone is formed by the oxidative loss of the side chain at C-17 and reduction of ring A. 

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