17a-Hydroxypregnenolone

The 17,20-glycol grouping (with or without an additional C-21 alcohol) can be cleaved to the 17-ketone by any of the four reagents. However, the presence of a 20-ketone has a marked influence on reactivity. Thus, 17a-hydroxy-20-ketones lacking additional oxygenation at C-21 are readily cleaved only by chromium trioxide. A recent report,however, claims that 17a-hydroxypregnenolone 3-acetate can be quantitatively cleaved to dehydroepiandrosterone acetate using lead tetraacetate in an aprotic solvent... 

Recently, Voogt et al. [91] have reported on the d5-pathway in steroid metabolism of Asterias rubens. These workers established the existence of the d5-pathway (Scheme 20), analogous to the pathway found in mammals this conclusion was based on the observation that radiolabeled cholesterol (1) was converted to pregnenolone (112), 17a-hydroxypregnenolone (141), and androstenediol (142). Labeled pregnenolone was converted additionally to progesterone (129). Androstenediol (142) was the main metabolite of de-hydroepiandrosterone (143), a reaction catalyzed by 17/i-hydroxysteroid dehydrogenase (17/1-HSD). The metabolic conversion of androstenedione (131) to testosterone (132) is also mediated by 17/J-HSD and is related to... 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Cortisol is synthesized from pregnenolone by two pathways in the fasciculata and reticularis zones of the adrenal gland. For simplicity, only one pathway is shown in Figure 51-6. The enzyme 17a-hydroxylase and the enzyme complex A -3P-hydroxysteroid dehydrogenase A ketosteroid isomerase located in the endoplasmic reticulum will synthesize 17a-hydroxyprogesterone from either 17a-hydroxypregnenolone or progesterone. Hydroxylation of this compound by the... 

The zona fasciculata and zona reticularis produce and secrete 17a-hydroxypregnenolone, the main precursor of the adrenal androgens. A microsomal 17a-hydroxylase/ C-17,20-lyase (P-450ci7) enzyme converts 17a-... 

A deficiency of ll -hydroxylase is the second most common form of CAH, with an incidence of 1 per 100,000 births, and is associated with manifestations of virilization, elevated concentrations of plasma androstenedione and DHEA-S, and hypertension. The mineralocorticoid-induced hypertension is caused by an elevation of DOC 11-deoxycortisol concentrations are markedly raised in subjects with this enzyme defect,The major distinguishing characteristic of this disorder from 21-hydroxylase deficiency, besides the elevated plasma concentrations of 11-deoxycortisol, is hypertension elicited by the salt retention caused by increased concentrations of DOC, A deficiency of 3 -hydroxysteroid dehydrogenase-isomerase has been reported and leads to an elevation in the ratio of 17a-hydroxypregnenolone to that of 17a-hydroxyprogesterone and to an increased ratio of DHEA to androstenedione. In severe forms of this rare disorder, female infants have pseudohermaphroditism, and male infants present with incomplete masculinization. Patients with this disorder usually present in early infancy with complete adrenal insufficiency including salt wasting. A late-onset form has also been reported in patients with premature pubarche with hirsutism, acne, and menstrual irregularities. The... 

The concertedness of the P450 17A1 lyase reaction has been examined, and both the studies both reached the conclusion that much of the 17a-hydroxypregnenolone dissociates In one of the studies, the authors concluded that the off-rate was an important factor in determining the balance between 17-hydroxypregnenolone and DHEA. Exactly how fej would control this rate, which was modeled to be rather slow (2.6-29min ), is unclear, unless the effect is on the protein conformation. However, a classic burst kinetic experiment was not done in the cited work and the hypothesis remains to be addressed in more detail. 

Soucy, P. and V Luu-The (2000). Conversion of pregnenolone to DHEA by human 17a-hydroxy-lase/17,20-lyase (P450c 17). Evidence that DHEA is produced from the released intermediate, 17a-hydroxypregnenolone. Eur. J. Biochem. 267, 3243-3247. 

The lyase reaction is more prominent in adrrlt adrenals with the steroids (than A" i.e., with 17a-hydroxypregnenolone than 17a-... 

The 3p hydroxy-5-ene steroids 17a hydroxy pregnenolone and dehydroepi-androsterone form the 3-mono-HFB derivatives. In case of dehydroepiandroster-one, we chose m/z 270.1 [M-214]+ in SIM. This is the base peak of the spectrum and results from loss of the 3-hydroj group. Regarding 17a-hydroxypregnenolone, we monitored m/z 467.1 [M 43]+, again the base peak of the spectrum. It represents the steroid nucleus after loss of the 17a-hydroxy group and the side chain. 

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