Abstract
Cytochrome P4507B1 7α-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5α-androstane-3β,17β-diol (Adiol). 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts 7α- and 7β-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [ 3H]-labelled 7β-hydroxy-DHEA, 7β-hydroxy-EpiA and 7β-hydroxy-Adiol showed the 3H-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 11β-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7α- or 7β-hydroxylated derivatives resulted from either turned or flipped forms. 11β-HSD1 incubation in H 2 18O medium with each 7-hydroxysteroid did not incorporate 18O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7α- and 7β-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 7β-hydroxy-EpiA production and its effects in triggering the resolution of inflammation.
Published Version
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