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 [(3)H]-labelled 7β-hydroxy-DHEA, 7β-hydroxy-EpiA and 7β-hydroxy-Adiol showed the (3)H-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)(18)O medium with each 7-hydroxysteroid did not incorporate (18)O 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.
三月 1, 2009