Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: nuclear and microsomal 11beta-hydroxysteroid dehydrogenases.

The 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) activates glucocorticoids (GC) by reversibly converting 11-keto-GC to 11-hydroxy-GC, while 11betaHSD2 and 11betaHSD3 only catalyzes the reverse reaction. Recently, rat and human 11betaHSDs were shown to interconvert 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (7alpha- or 7beta-OH-DHEA) with 7-oxo-DHEA. We report that pig kidney microsomes (PKMc) and nuclei (PKN) oxidize 7alpha-OH-DHEA to 7-oxo-DHEA at higher rates with NAD+, than with NADP+. Corticosterone (CS), dehydrocoticosterone (DHC), 11alpha- and 11beta-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD+-dependent reaction. Conversely, CS oxidation was not inhibited by 7alpha-OH-DHEA or 7-oxo-DHEA. PKMc and PKN did not convert 7-oxo-DHEA to 7-OH-DHEA with either NADPH or NADH. Finally, PKN contained a high affinity, NADPH-dependent 11betaHSD that reduces DHC to CS. The GC effects on interconversion of DHEA metabolites may have clinical significance, since DHEA and its 7-oxidized derivatives have been proposed for treatment of human autoimmune and inflammatory disorders.