Inter-conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone by the human 11beta-hydroxysteroid dehydrogenase type 1.
The dehydroepiandrosterone (DHEA) 7alpha-hydroxylation in humans takes place in the liver, skin, and brain. These organs are targets for the glucocorticoid hormones where 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisone through its reduction into cortisol. The putative interference of 7alpha-hydroxy-DHEA with the 11beta-HSD1-catalyzed reduction of cortisone into cortisol has been confirmed in preliminary works with human liver tissue preparations of the enzyme demonstrating the transformation of 7alpha-hydroxy-DHEA into 7-oxo-DHEA and 7beta-hydroxy-DHEA. However, the large production of 7beta-hydroxy-DHEA could not be explained satisfactorily. Therefore our objective was to study the role in the metabolism of oxygenated DHEA by recombinant human 11beta-HSD1 expressed in yeast. The 7alpha- and 7beta-hydroxy-DHEA were each oxidized into 7-oxo-DHEA with quite dissimilar K(M) (70 and 9.5 microM, respectively) but at equivalent V(max). In contrast, the 11beta-HSD1-mediated reduction of 7-oxo-DHEA led to the production of both 7alpha- and 7beta-hydroxy-DHEA with equivalent K(M) (1.1 microM) but with a 7beta-hydroxy-DHEA production characterized by a significantly greater V(max). The 7alpha-hydroxy-DHEA produced by the cytochrome CYP7B1 in tissues may exert anti-glucocorticoid effects through interference with the 11beta-HSD1-mediated cortisone reduction.
Muller
Caroline
C
Laboratoire de Biologie, EA-3199, Conservatoire National des Arts et Métiers, 2 rue Conté, 75003 Paris, France.
Pompon
Denis
D
Urban
Philippe
P
Morfin
Robert
R
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002855:Chromatography, Thin Layer; D003348:Cortisone / Q000378:metabolism; D017931:DNA Primers; D003687:Dehydroepiandrosterone / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007700:Kinetics; D013379:Substrate Specificity
D017931:DNA Primers; D003687:Dehydroepiandrosterone; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone; D006854:Hydrocortisone