17a-hydroxylase

Cortisol synthesis requires three hydroxylases located in the fasciculata and reticularis zones of the adrenal cortex that act sequentially on the Cjy, C21, and Cjj positions. The first two reactions are rapid, while Cu hydroxylation is relatively slow. If the C, position is hydroxylated first, the action of 17a-hydroxylase is impeded and the mineralocorticoid pathway is followed (forming corti-... 

Akhtar M, DL Corina, SL Miller, AZ Shyadehi (1994) Incorporation of label from into acetate during side-chain cleavage catalyzed by cytochrome P-450j7 (17a-hydroxylase-17,20-lyase). J Chem Soc Perkin Trans T. 263-267. 

BARNES, H.J., ARLOTTO, M.P., WATERMAN, M.R., Expression and enzymatic activity of recombinant cytochrome P450 17a-hydroxylase in Escherichia coli, Proc. Natl. Acad. Sci. USA, 1991,88, 5597-5601. 

Fig. 9.5 Structural formula of the 17a-hydroxylase-17,20-lyase inhibitor MH61.

BIOMINERALIZATION STEROID 11/3-HYDROXYLASE STEROID 17a-HYDROXYLASE STEROID 21-HYDROXYLASE Steroids,... 

Serum steroid hormonal profiles by reversed-phased liquid chromatography in patients with 17a-hydroxylase deficiency. (158)... 

Abiraterone is the newest of the steroid synthesis inhibitors to enter clinical trials. It blocks 17a-hydroxylase (P450cl7) and 17,20-lyase (Figure 39-1), and predictably reduces synthesis of cortisol and gonadal steroids in the adrenal and gonadal steroids in the gonads. A compensatory increase occurs in ACTH and aldosterone synthesis, but this can be prevented by concomitant administration of dexamethasone. Abiraterone is an orally active steroid prodrug and has been studied in the treatment of refractory prostate cancer. 

Spironolactone, a competitive inhibitor of aldosterone (see Chapter 15), also competes with dihydrotestosterone for the androgen receptors in target tissues. It also reduces 17a-hydroxylase activity, lowering plasma levels of testosterone and androstenedione. It is used in dosages of 50-200 mg/d in the treatment of hirsutism in women and appears to be as effective as finasteride, flutamide, or cyproterone in this condition. 

Fig. 3. Gonadal steroid biosynthetic pathway and the catalytic enzymes 1) cytochrome P-450scc 2) -hydroxysteroid dehydrogenase 3) 17a-hydroxylase (P-450scc17) 4) 17,20-desmolase or 17,20-lyase 5) 17(3-hydroxysteroid dehydrogenase 6) 5a-reductase and 7) P-450 aromatase.

Honour JW, Tourniaire J, Biglieri EG, Shackleton CHL (1978) Urinary steroid excretion in 17a-hydroxylase deficiency. J Steroid Biochem 9 495-505... 

Spironolactone exhibits antiandrogenic effects in males and females. It decreases testosterone biosynthesis by inhibiting steroid 17a-monooxygenase (17a-hydroxylase) activity, possibly secondary to destruction of microsomal cytochrome P-450 in tissues with high steroid 17a-monooxygenase activity (testes, adrenals) [65],... 

Fig. 2. Pathway of biosynthesis of the glucocorticoid, cortisol, in the adrenal cortex. Cholesterol, from stores in cholesteryl esters or from other sources (see text) is converted via mitochondrial cytochrome P-450SCC (cholesterol side-chain cleavage enzyme) to pregnenolone, which then is successively converted by the microsomal enzymes cytochrome P-450,7 (17a-hydroxylase), 3 j8-hydroxysteroid dehydrogenase/ isomerase and cytochrome P-450c2, (21-hydroxylase) to 11-deoxycortisol, followed by conversion by the mitochondrial cytochrome P-450ll(3 (11/3-hydroxylase) to cortisol. The short-term action of ACTH in stimulation of steroidogenesis is to increase the availability of cholesterol for conversion by cytochrome P-450scc. From Ref. 9.

Fig. 7. Hypothesis for the action of ACTH in increasing the level of steroidogenic enzymes, in this case 17a-hydroxylase. In this model, cyclic AMP activates cyclic AMP-dependent protein kinase which by a series of unknown steps results in the accumulation of mRNA coding for a regulatory protein (17a-RP). After translation of this mRNA, the 17a-RP is hypothesized to translocate to the nucleus, where it activates the transcription of the cytochrome /M50,7 gene. This is one of several hypotheses which account for the sensitivity of cytochrome P-450 gene expression to inhibition of protein synthesis. From Ref. 27.

Why do patients with 21-hydroxylase deficiency exhibit low blood pressure whereas those with 17a-hydroxylase deficiency exhibit high blood pressure ... 

The properties of the 11a- and 17a-hydroxylases from induction cultures of Rhizopus nigricans have been reported.313 The inhibition of 11/3-hydroxylase by... 

The pattern of inhibition of 17a-hydroxylase exhibited by metyrapone lends further support to the hypothesis that cytochrome P450 is involved in the enzyme system319 whilst the effect of administration of spironolactone on the cytochrome P450 content and 17a-hydroxylase activity in adrenal tissue has shown that decreases in both of these factors occur only in animals that produce predominantly cortisol rather than corticosterone.320 18-Hydroxylation of deoxycorticosterone has been demonstrated in rat and bovine mitochondrial preparations and in reconstituted systems obtained from these fractions.321 In all cases, 18-hydroxylation was accompanied by 11/8-hydroxylation, and the study indicated that very similar types of cytochrome P450 were involved in both hydroxylation systems. 

P450 XVIIA1 17a Noninducible Cydopropylamino androstenol Progesterone 17a-hydroxylase... 

Steroid 17a-Hydroxylase/C17 20 Lyase (Cytochrome P4502ikc) (Schatzman et al., 1988)... 

Bilateral adrenal hyperplasia Secondary hyperaldosteronism Hyperreninemic hyperaldosteronism (hypertension) Congenital adrenal hyperplasia (due to adrenal enzyme deficiencies in cortisol production [11 3- or 17a-hydroxylase])... 

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-... 

When the condition of 17a-hydroxylase deficiency occurs, the production of cortisol and sex steroids (except for progesterone) is impaired and the production of miner-alocorticoids increased (see Figure 51-4, Chapter 51). With tliis deficiency, plasma concentrations of corticosterone, 11 - deoxycorticosterone, progesterone, and pregnenolone are elevated. Boys exhibit pseudohermaphroditism and deficiency in development of secondary sex characteristics. 

A 17a-hydroxylase deficiency is a rare form of CAH that is associated with delayed puberty, primary amenorrhea, and hypertension. These patients have a 46 XX karyotype with elevated gonadotropins, low sex steroids, hypertension, and hypokalemia (see Chapter 51). ... 

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