Regulation of human 3ß-hydroxysteroid dehydrogenase type 2 by adrenal corticosteroids and product-feedback by androstenedione in human adrenarche.
J Pharmacol Exp Ther
; 352(1): 67-76, 2015 Jan.
Article
en En
| MEDLINE
| ID: mdl-25355646
ABSTRACT
In human adrenarche during childhood, the secretion of dehydroepiandrosterone (DHEA) from the adrenal gland increases due to its increased synthesis and/or decreased metabolism. DHEA is synthesized by 17α-hydroxylase/17,20-lyase, and is metabolized by 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSD2). In this study, the inhibition of purified human 3ßHSD2 by the adrenal steroids, androstenedione, cortisone, and cortisol, was investigated and related to changes in secondary enzyme structure. Solubilized, purified 3ßHSD2 was inhibited competitively by androstenedione with high affinity, by cortisone at lower affinity, and by cortisol only at very high, nonphysiologic levels. When purified 3ßHSD2 was bound to lipid vesicles, the competitive Ki values for androstenedione and cortisone were slightly decreased, and the Ki value of cortisol was decreased 2.5-fold, although still at a nonphysiologic level. The circular dichroism spectrum that measured 3ßHSD2 secondary structure was significantly altered by the binding of cortisol, but not by androstenedione and cortisone. Our import studies show that 3ßHSD2 binds in the intermitochondrial space as a membrane-associated protein. Androstenedione inhibits purified 3ßHSD2 at physiologic levels, but similar actions for cortisol and cortisone are not supported. In summary, our results have clarified the mechanisms for limiting the metabolism of DHEA during human adrenarche.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Retroalimentación Fisiológica
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Inhibidores Enzimáticos
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Adrenarquia
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17-Hidroxiesteroide Deshidrogenasas
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Androstenodiona
Límite:
Humans
Idioma:
En
Revista:
J Pharmacol Exp Ther
Año:
2015
Tipo del documento:
Article