Steroid 17a-hydroxylase

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

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

Kossor, D.C., S. Kominami, S. Takemori and H.D. Colby. Role of the steroid 17a-hydroxylase in spironolactone-mediated destruction of adrenal cytochrome P450. Mol. Pharmacol. 40 321-325, 1991. 

Cyclopropylamino)-androst-5-en-3(3-ol, a selective mechanism-based inhibitor of cytochrome P45017a(steroid 17a-hydroxylase/C 17-20 lyase). Biochem. Biophys. Res. Commun. 162, 1571-1577. 

Chung, B., J. Picado-Leonard, M. Haniu, M. Bienkowski, RE Hall, J.E. Shively etal. (1987). Cytochrome P450c 17 (steroid 17a-hydroxylase/17, 20 lyase) Cloning of human adrenal and testis cDNAs indicates the same gene is expressed in both tissues. Proc. Natl. Acad. Sci. USA 84,407-411. 

K. Kangawa, and S. Matsukura (1997). A 5 -splice site mutation in the cytochrome P450 steroid 17a-hydroxylase gene in 17a-hydroxy-lase deficiency. J. Clin. Endocrinol. Metab. 82, 1934-1938. 

FIGURE 58-1 Pathway of synthesis of testosterone in the Leydig cells of the testes. Leydig cells express steroid 17a-hydroxylase (CYP17), which carries out sequential 17-hydroxylation and C17-20 lyase reactions in the biosynthetic pathway to produce androgens. Bold arrows indicate favored pathways. 

Cells of the zona fasciculata have fewer receptors for Angll and express two enzymes, steroid 17a-hydroxylase (CYP17) and 11/3-hydroxylase (CYPllBl), which catalyze the production of glucocorticoids. In the zona reticularis, CYP17 carries out a second C17-20 lyase reaction that converts C21 corticosteroids to C19 androgen precursors. 

In the next reaction steps, the enzymes 3)S-hydroxy-A -steroid dehydrogenase, steroid A-isomerase and steroid 17a-hydroxylase are involved. Oxidation at C-3 and double bond migration leads to progesterone, the hormone of the corpus luteum. Afterwards, the C-17 position is hydroxylated to give 17 -hydroxyprogesterone. The reverse reaction sequence is also known and... 

Putative cytochrome 450-catalyzed MFO activities have been identified or indicated towards a number of endogenous substrates, viz. steroid 17a-hydroxylase... 

Picado-Leonard J, Miller WL (1987) Cloning and sequence of the human gene encoding P450cl7 (steroid 17a-hydroxylase/17,20 lyase) similarity to the gene for P450c21. DNA 6 439 8... 

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. 

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],... 

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). ... 

Fig. 3. Summary of key mechanisms of action through which a model adrenotoxicant (indicated by a black star) could disrupt the synthesis of corticosteroids. References presenting data in support of this model are given in the text. ACTH, adrenocorticotropic hormone Rc, receptor G, G-protein AC, adenylyl cyclase Ca, calcium ATP, adenosine triphosphate cAMP, cyclic adenosine monophosphate PKA, protein kinase A StAR, Steroid acute regulatory protein SCC, P450SCO, cholesterol side chain cleaving enzyme 11/3, 11/3-hydroxylase 17a, 17a-hydroxylase 3/3-HSD, 3/3-hydroxysteroid-5A-steroid dehydrogenase C21, 21-hydroxylase ER, endoplasmic reticulum.

The Sex Steroid Pathway Is Initiated by 17a-Hydroxylase/17,20-Lyase (CYP17)... 

This can be due to defects in several enzyme systems required for the formation of cortisol (Fig. 8), but in all cases the inadequate level of cortisol in the blood causes corticotropin to be secreted by the pituitary in increasing amount this in turn causes hyperplasia of the adrenal glands with overproduction of those steroids not affected by the enzyme block. The most common deficiency is in 21-hydroxylase, but deficiencies have also been reported in infants and children of 3j8-HSD, lljff-hydroxy-lase, and cholesterol desmolase, and in older infants of 17a-hydroxylase (N4). 

Enzymes of the biosynthetic pathway of steroid hormones can also be demonstrated effectively in immunohistochemical formats. Among the enzymes that have been localized are P450scc (cholesterol side chain cleavage), 3 3-hydroxysteroid dehydrogenase, 21-hydroxylase, 17a-hydroxylase, and lip-hydroxylase. " To date, however, there have been relatively few studies evaluating antibodies to these enzymes as diagnostic reagents. 

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