title: Dehydroepiandrosterone 7alpha-hydroxylation in human tissues: possible interference with type 1 11beta-hydroxysteroid dehydrogenase-mediated processes.
abstract: Dehydroepiandrosterone (DHEA) is 7alpha-hydroxylated by the cytochome P450 7B1 (CYP7B1) in the human brain and liver. This produces 7alpha-hydroxy-DHEA that is a substrate for 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which exists in the same tissues and carries out the inter-conversion of 7alpha- and 7beta-hydroxy-DHEA through a 7-oxo-intermediary. Since the role of 11beta-HSD1 is to transform the inactive cortisone into active cortisol, its competitive inhibition by 7alpha-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 CYP7B1 and 11beta-HSD1. Human skin was selected then and used to test its ability to produce 7alpha-hydroxy-DHEA, and to test the interference of 7alpha- and 7beta-hydroxy-DHEA and 7-oxo-DHEA with the 11beta-HSD1-mediated oxidoreduction of cortisol and cortisone. Immuno-histochemical studies showed the presence of both CYP7B1 and 11beta-HSD1 in the liver, skin and tonsils. DHEA was readily 7alpha-hydroxylated when incubated using skin slices. A S9 fraction of dermal homogenates containing the 11beta-HSD1 carried out the oxidoreduction of cortisol and cortisone. Inhibition of the cortisol oxidation by 7alpha-hydroxy-DHEA and 7beta-hydroxy-DHEA was competitive with a Ki at 1.85+/-0.495 and 0.255+/-0.005 microM, respectively. Inhibition of cortisone reduction by 7-oxo-DHEA was of a mixed type with a Ki at 1.13+/-0.15 microM. These findings may support the previously proposed native anti-glucocorticoid paradigm and suggest that the 7alpha-hydroxy-DHEA production is a key for the fine tuning of glucocorticoid levels in tissues.
authors.affiliation: Laboratoire de Biotechnologie, EA-3199, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hennebert
authors.forename: Sonia
authors.initials: S
authors.lastname: Chalbot
authors.forename: Severine
authors.initials: S
authors.lastname: Alran
authors.forename: Robert
authors.initials: R
authors.lastname: Morfin
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D003348:Cortisone / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072474:Cytochrome P450 Family 7; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D006900:Hydroxylation; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D010084:Oxidation-Reduction; D012867:Skin / Q000201:enzymology / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism*
chemical_list: C002914:7-oxodehydroepiandrosterone; D003687:Dehydroepiandrosterone; C003587:7-hydroxydehydroepiandrosterone; D003577:Cytochrome P-450 Enzyme System; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C499571:CYP7B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone