Dehydroepiandrosterone 7α-hydroxylation in human tissues:: Possible interference with type 1 11β-hydroxysteroid dehydrogenase-mediated processes

Dehydroepiandrosterone (DHEA) is 7 alpha-hydroxylated by the cytochome P450 713 1 (CYP7B 1) in the human brain and liver, This produces 7 alpha-hydroxy-DHEA that is a substrate for I I P-hydroxy steroid dehydrogenase type I (I I P-HSD I) which exists in the same tissues and carries out the inter-conversion of 7 alpha- and 7 beta-hydroxy-DHEA through a 7-oxo-intermediary. Since the role of I I P-HSD I is to transform the inactive cortisone into active cortisol, its competitive inhibition by 7 alpha-hydroxy-DHEA may support the paradigm of native anti-glucocorticoid arising from DHEA. Therefore, our objective was to use human tissues to assess the presences of both CYP713 I and 11 beta-HSD1. Human skin was selected then and used to test its ability to produce 7 alpha-hydroxy-DHEA, and to test the interference of 7 alpha- and 7 beta-hydroxy-DHEA and 7-oxo-DHEA with the I I P-HSD I-mediated oxidoreduction of cortisol and cortisone. Immuno-histochemical studies showed the presence of both CYP713 I and 11 beta-HSDI in the liver, skin and tonsils. DHEA was readily 7a-hydroxylated when incubated using skin slices. A S9 fraction of dermal homogenates containing the 11P-HSD1 carried out the oxidoreduction of cortisol and cortisone. Inhibition of the cortisol oxidation by 7(x-hydroxy-DHEA and 7 beta-hydroxy-DHEA was competitive with a Ki at 1.85 +/- 0.495 and 0.255 +/- 0.005 [LM, respectively. Inhibition of cortisone reduction by 7-oxo-DHEA was of a mixed type with a Ki at 1.13 +/- 0.15 mu M. These findings may support the previously proposed native anti-glucocorticoid paradigm and suggest that the 7 alpha-hydroxy-DHEA production is a key for the fine tuning of glucocorticoid levels in tissues. (C) 2007 Elsevier Ltd. All rights reserved.