Cytochrome P450c17: Regulation of Gene Expression and Enzyme Function at the Bifurcation in Steroid Hormone Synthesis

Kühn‐Velten, W. Nikolaus

doi:10.1007/978-3-642-77763-9_43

Cited by 3 publications

(5 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synthetic pathways of progesterone and its hydroxy derivatives. The expression levels of steroidogenic isoforms such as CYP7, CYP11, CYP17, CYP19, and CYP21, are regulated by steroid hormones (2)(3)(4)(5)(6)(7). In fact, the total levels of progesterone and hydroxyprogesterones detected in this study were comparable to the levels of progesterone reported previously (14).…”

Section: Discussionsupporting

confidence: 81%

Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain

et al. 2001

View full text Add to dashboard Cite

The existence of cytochrome P450 2D isoforms in the brain has been demonstrated, although their physiological functions remain to be elucidated. In this study we demonstrated that recombinant rat cytochrome P450 2D1 and 2D4 and human cytochrome P450 2D6 possess progesterone 6 beta- and 16 alpha- hydroxylation activities; 2 beta- and 21-hydroxylation activities; and 2 beta-, 6 beta-, 16 alpha- and 21-hydroxylation activities, respectively. Cytochrome P450 2D4 had the lowest K(m) value and the highest maximum velocity value toward these activities. Progesterone 2 beta- and 21-hydroxylation activities were also detected in rat brain microsomes, and these activities were completely inhibited by anticytochrome P450 2D antibodies. The presence of endogenous 2 beta- and 21-hydroxyprogesterones in rat brain tissues was also demonstrated. The mRNAs of cytochrome P450 2D4, CYP11A, and 3 beta-hydroxysteroid dehydrogenase were detected in the rat brain, suggesting that progesterone was generated from cholesterol by CYP11A and 3 beta-hydroxysteroid dehydrogenase and then underwent hydroxylation to hydroxyprogesterones by cytochrome P450 2D4 in rat brain. Collectively, our findings support the idea that cytochrome P450 2D may be involved in the regulation (metabolism and/or synthesis) of endogenous neuroactive steroids, such as progesterone and its derivatives, in brain tissues.

show abstract

Section: Discussionsupporting

confidence: 81%

Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain

et al. 2001

View full text Add to dashboard Cite

show abstract

“…CYP17 is the rate-limiting enzyme of the second compartment of androgen formation at least during stimulation of steroidogenesis (see Figs. 1 and 2), and it represents the branchpoint in steroid hormone processing (Rommerts, 1990;Kühn-Velten et al, 1991;Kühn-Velten, 1993): The educts (gestagens) are either transformed to androgens, or the hydroxylated intermediates are released and eventually (in the adrenals) channelled into glucocorticoid formation. Thus, this enzyme controls the efficiency of androgen formation from precursors (Kühn-Velten et al, 1991), and its susceptibility to multiple regulatory strategies has to be seen in connection with this fact (Kühn-Velten, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…CYP1 lA (P45Ocscc: cholesterol monooxygenase or side-chain cleavage enzyme) within the mitochondna and CYP17 (P450c17: steroid-17a-monooxygenase or hydroxylase and steroid-Cl 7,20-aldolase or lyase) within the smooth endoplasmic reticulum. Though both testicular enzymes are targets for cAMP-mediated stimulation by LH or hCG, time-courses of activity changes differ in that enhancement of gene transcription is preceded by a phase of down-regulation in the case of CYP17 which is not seen with CYP1 lA (Kühn-Velten, 1990;Rommerts, 1990;Edwards et al, 1991;Kühn-Velten, 1993).…”

Section: Infroductionmentioning

confidence: 99%

Rapid down-regulation of testicular androgen biosynthesis at increased environmental temperature is due to cytochrome P450c17 (CYP17) thermolability in Leydig cells, but not in endoplasmic reticulum membranes

Kühn‐Velten¹

2009

Exp Clin Endocrinol Diabetes

Self Cite

View full text Add to dashboard Cite

To identify possible molecular targets in moderate heat-induced, short-term derangements of rat testicular endocrine function, rates of androgen and precursor biosynthesis and key enzyme concentrations were compared at 38 degrees C (normal body core temperature) and 31 degrees C (normal scrotal temperature) in three in-vitro models of decreasing complexity and increasing specificity. In purified Leydig cells and similarly in decapsulated testes, gross testosterone secretion was by 20% higher at 38 degrees C under basal conditions and during the initial phase of stimulation with hCG or cAMP; longer (> 1 hour) exposure to the elevated temperature resulted in a marked decrease (52% after 3 hours) of testosterone response to hCG or cAMP as compared to the corresponding rates at 31 degrees C. This phenomenon was neither due to the development of hormone resistance at the receptor level nor to restricted cholesterol supply and turnover nor to increased testosterone accumulation. Whereas mitochondrial CYP11A (cytochrome P450cscc: cholesterol monooxygenase) was absolutely temperature-insensitive in all systems tested, CYP17 (cytochrome P450c17: steroid-17 alpha-monooxygenase/C17, 20-aldolase) in the smooth endoplasmic reticulum responded with a 57% loss in whole testes and 39% loss in purified Leydig cells upon a 3-hour temperature elevation from 31 degrees C to 38 degrees C. In contrast, CYP17 was stable (4% loss) when tested directly in microsomal membranes. It is concluded that CYP17, but not CYP11A, is very sensitive towards even moderate elevation of environmental temperature, and that this apparent lability is not an intrinsic property of the enzyme protein but rather mediated by heat-activated intracellular factors.

show abstract

“…In the zona reticularis of the human adrenal, DHEA is predominantly synthesized via the so‐called 5‐ene pathway, i.e. pregnenolone (pregn‐5‐en‐3β‐ol‐20‐one) is the preferred substrate for the rate‐limiting enzyme of the late steroidogenic pathway [15,16]. This is the bifunctional CYP17, another member of the superfamily of CYP proteins, which controls a bifurcation in steroid hormone synthesis: For human adrenal androgen formation, the sequence catalyzed by this enzyme is pregnenolone → 17α‐hydroxypregnenolone → DHEA, so both reactions are performed at one single active centre where most of the 17α‐hydroxylated intermediate is retained during the catalytic process (branch I).…”

Section: Synthesis and Metabolism Of Dhea And Dheasmentioning

confidence: 99%

“…3β‐HSDH/I activity and the second one being the degree of 17α‐hydroxypregnenolone retention by CYP17, which is dependent on the rate of electron transfer from the cytochrome reductase to CYP17 (Kühn‐Velten and Vogt, submitted). It is interesting to note that during adrenarche, 3β‐HSDH/I activity as related to CYP17 decreases; in addition, it has been hypothesized that adrenarche coincides with increased CYP17 phosphorylation resulting in improved substrate binding and intermediate retention due to accelerated electron transfer [16–18].…”

Section: Synthesis and Metabolism Of Dhea And Dheasmentioning

confidence: 99%

Intracrinology and the local enzymatic control of hormone distribution and metabolism: dehydroepiandrosterone does not just act as a prohormone for androgens and estrogens

Kühn‐Velten

2000

Eur J Clin Investigation

Self Cite

View full text Add to dashboard Cite

The study of subcellular environments for the interaction of biomolecules and observations of certain features of hormone actions have nourished the concept of 'intracrinology', which describes hormone actions within a singular cell, in contrast to the well-described autocrine, paracrine and endocrine fashion. Synthesis and metabolism of DHEA make it a likely candidate for intracrine actions in target tissues. Recent experimental findings are reviewed in this context.

show abstract

Cytochrome P450c17: Regulation of Gene Expression and Enzyme Function at the Bifurcation in Steroid Hormone Synthesis

Cited by 3 publications

References 45 publications

Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain

Progesterone Oxidation by Cytochrome P450 2D Isoforms in the Brain

Rapid down-regulation of testicular androgen biosynthesis at increased environmental temperature is due to cytochrome P450c17 (CYP17) thermolability in Leydig cells, but not in endoplasmic reticulum membranes

Intracrinology and the local enzymatic control of hormone distribution and metabolism: dehydroepiandrosterone does not just act as a prohormone for androgens and estrogens

Contact Info

Product

Resources

About