11 -Deoxycorticosterone biosynthesis

FI6URE28 1. Biosynthesis and metabolism of neurosteroids. Solid arrows refer to enzyme activities demonstrated in the central nervous system (CNS) dashed arrows refer to enzyme activities not demonstrated in the CNS. allo-THDOC = allotetrahydro-deoxycorticosterone 5a-DHDOC = 5a-dihydro-deoxycorticosterone 5a-DHP = 5a-dihydro-progesterone. 

Primary aldosteronism usually results from the excessive production of aldosterone by an adrenal adenoma. However, it may also result from abnormal secretion by hyperplastic glands or from a malignant tumor. The clinical findings of hypertension, weakness, and tetany are related to the continued renal loss of potassium, which leads to hypokalemia, alkalosis, and elevation of serum sodium concentrations. This syndrome can also be produced in disorders of adrenal steroid biosynthesis by excessive secretion of deoxycorticosterone, corticosterone, or 18-hydroxycorticosterone—all compounds with inherent mineralocorticoid activity. 

Progesterone is synthesized from either cholesterol or alkylated plant sterols by a pathway similar to that in animals. Hydroxylation at C-20 and C-22 is a prerequisite for removal of the C-6 residue of the side chain (A, B, C, Fig. 16). The product pregnenolone is then reduced to progesterone (D, Fig. 16). Traces of oestrone, testosterone, deoxycorticosterone and closely related compounds have been found in plants but nothing is known of their biosynthesis. 

The past decade has shown that hydrocarbon desaturation is not uncommon but, except in cases such as the biosynthesis of ergosterol, it generally accounts for a minor proportion of the metabolic products. The earliest reported example of P450-mediated hydrocarbon desaturation appears to be the conversion of lindane (1,2,3,4,5,6-hexachloro-cyclohexane) to 1,2,3,4,5,6-hexachlorocyclohex-ene, but the known hydrocarbon desaturation reactions now include the A -desaturation of androstenedione and deoxycorticosterone by adrenal mitochondria, the oxidation of dihydronaphthalene to naphthalene and 7,8-dihydrobenzo[a] pyrene to benzo[a]pyrene the conversion of warfarin to dehydrowarfarin ", the desaturation of lovostatin and simvastatin to the 6-exo-methylene... 

Similar strategies have been used to develop inhibitors that target the C-18 hydroxylation involved in the biosynthesis of aldosterone . Thus, aldosterone analogs with C-18 iodomethyl, chloromethyl, allyl, propargyl, vinyl, and methyl-thiomethyl functionalities have been synthesized and some have been found to irreversibly inactivate the enzyme. An active site-directed 18-acetylenic deoxycorticosterone [21 -hydroxy-13(-2-)propy-... 

Johnston, J.O., C.L. Wright, R.A. Bohnke, and P.R. Kastner (1991). Inhibition of aldosterone biosynthesis in primates by 18-acetylenic deoxycorticosterone. Endocrinology 128 (Suppl. Abstract 24). 

On the basis of in vitro studies using adrenal glomer-ulosa tissues two pathways have been proposed for aldosterone biosynthesis. One starts with progesterone as a precursor and involves 11-deoxycorticosterone and possibly 18-hydroxycorticosterone and corticosterone as intermediates and in the other pathway, corticosterone is bypassed, and the 18-hydroxylation precedes the 11-hydroxylations. 

Several compounds related to 32 were described as specific inhibitors of aldosterone biosynthesis vitro without altering deoxycorticosterone and corticosterone levels. 

Scheme 5.5 Possible multistep oxidation of deoxycorticosterone to aldosterone catalyzed by CYP11B2. Bold arrows indicate the experimentally confirmed biosynthesis pathway toward...

Ascorbic acid (L-3-keto-threo-hexuronic acid-7-lactone. Formula 6.18, I) is involved in hydro-xylation reactions, e. g., biosynthesis of catecholamines, hydroxyproline and corticosteroids (11-P-hydroxylation of deoxycorticosterone and 17-P-hydroxylation of corticosterone). Vitamin C is fully absorbed and distributed throughout the body, with the highest concentration in adrenal and pituitary glands. 

This is an inherited condition in which there is a deficiency of one of the enzymes of cortisol biosynthesis. The resulting low plasma cortisol levels result in high levels of ACTH production because of the absence of feedback control. This in turn results in the accumulation of androgens and cortisol precursors. The consequences of this are pseudohermaphroditism in the female child and virilization in the male child. Deficiencies of 3 -dehydrogenase, 21 -hydroxylase and 1 IjS-hydroxylase have been described. The most common is 21 -hydroxylase deficiency, in which there is abnormal sodium loss (the salt-losing syndrome), due to impaired aldosterone production. 11 -Hydroxylase deficiency results in the excess secretion of 11-deoxycorticosterone and since this is an active mineralocor-ticoid, salt and water retention and hypertension result. 

Hydroxylation has been studied only in terms of aldosterone biosynthesis. A detailed investigation of precursors of this mineralocorticoid has been conducted and is described in full by Ayres et al. (1960). Corticosterone is transformed somewhat more rapidly than deoxycorticosterone or progesterone (Fig. 18). 18-Hydroxydeoxycorticosterone has been isolated from incubations of rat adrenal sections in the presence of TPNH and oxygen (Peron, 1961). Its further conversion (11/3-hydroxylation) to aldosterone, however, has not been reported. 

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