Deoxycorticosterone, oxidation

Cortisol-Cortisone Conversion. Under normal conditions, this equilibrium slightly favors the oxidized compound. Similarly, the conversion of corticosterone to 11-deoxycorticosterone is also mediated by the liP-hydroxysteroid dehydrogenase enzyme system and requites NAD(P) /NAD(P)H. This conversion is especially important both in the protection of the human fetus from excessive glucocorticoid exposure, and in the protection of distal nephron mineral ocorticoid receptors from glucocorticoid exposure (14). The impairment of this conversion is thought to result in hypertension associated with renal insufficiency (15). 

Wittig-Horner reaction (see p. 241). Photolysis of the nitrite of the 21-chloro-20-hydroxy-compound (194) gave the 18-oximino-compound (195) which on Jones oxidation was converted into the chlorolactone (196). Hypoiodite reaction of the 21-chloro-20-hydroxy-compound (194) also gives the chloro-lactone (196) which with modification gives 18-hydroxy-11-deoxycorticosterone (see also ref. 198). 

Galisteo M, Garcia-Saura MF, Jimenez R, Villar IC, Zarzuelo A, Vargas F, Duarte J. 2004. Effects of chronic quercetin treatment on antioxidant defence system and oxidative status of deoxycorticosterone acetate-salt-hypertensive rats. Mol Cell Biochem 259 91-99. 

If progesterone is directly acted on by 2l-hydroxylu.se (Cyp21). 11 -deoxycorticosterone is produced, a precursor lo the mineralocorticoid aldosterone. In tissues where aldosterone is synthesized, the multifunctional enzyme aldosterone synthase (Cypl IB2) mediates the hydroxylalion at Cl i as well as the two-step oxidation ofCIS lo an aldehyde, providing aldo.sicronc. which exists predominantly in the cyciic hcmiacclal form. 

Aldosterone is a by-product of the 21-hydroxylation of pregnenolone to form deoxycorticosterone. The oxidation of 18-hydroxycorticosterone to aldosterone is a unique feature of the zona glomerulosa, explaining why aldosterone is not affected during disease processes limited to the fasciculata and/or reticularis. 

The excess production of 11-deoxycorticosterone and corticosterone by infants with an 18-oxidation defect is probably due to an excess production of angiotensin, the stimulant for aldosterone production (M20). Renin, produced by the juxtaglomerular cells in the kidneys, initiates the formation of angiotensin, and a loss of salt causes this substance to be produced in excessive amounts. Evidence for this has been obtained by Ulick et al. (Ul), who found an increased amount of renin in the plasma of their patients during sodium depletion experiments. 

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... 

P450 11B2 catalyzes the three-step conversion of 11-deoxycorticosterone to aldosterone, with 1 ip-hydroxylation, 18-hydroxylation, and 2-electron oxidation of the 18-carbinol (Figures 10.13 and 10.14). No other substrates are known. Information about the processivity of the human enzyme (i.e., extent of release of intermediate products) is not available at this time. 

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. 

B2 catalyzes the 1 lyff-hydroxylation of 11-deoxycorticosterone followed by 18-hydroxylation and 2-electron oxidation of the 18-alcohol to an aldehyde (Figs. 9.12 and 9.23). Changes in the gene can lead to corticosterone methyloxidase deficiency and hyperaldosteronism [47, 1980, 2055, 2056]. In the older literature, this P450 is sometimes termed P450 j . ... 

Strushkevich et al. [2019] have presented evidence arguing the three-step oxidation of deoxycorticosterone to aldosterone (Figs. 9.23b and 9.24) is a processive one, in that lly -cordcosterone was not oxidized to the product. However, the question has not been analyzed in the usual ways of addressing these questions, e.g., with time course and pulse-chase experiments. 

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

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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