Epimerase activity of the human 11β-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids

Cytochrome P4507B1 7 alpha-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5 alpha-androstane-3 beta,17 beta-diol (Adiol). 11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) interconverts 7 alpha- and 7 beta-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [H-3]-labelled 7 beta-hydroxy-DHEA, 7 beta-hydroxy-EpiA and 7 beta-hydroxy-Adiol showed the H-3-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11 beta-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7 alpha- or 7 beta-hydroxylated derivatives resulted from either turned or flipped forms. 11 beta-HSD1 incubation in (H2O)-O-18 medium with each 7-hydroxysteroid did not incorporate O-18 in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7 alpha- and 7 beta-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser(170). The physiopathological importance of this epimerization process is related to 7 beta-hydroxy-EpiA production and its effects in triggering the resolution of inflammation. (C) 2009 Elsevier Ltd. All rights reserved.