Human liver S9 fractions: metabolism of dehydroepiandrosterone, epiandrosterone, and related 7-hydroxylated derivatives.

Dehydroepiandrosterone (DHEA) and 3beta-hydroxy-5alpha-androstan-17-one (epiandrosterone, EpiA) are both precursors for 7alpha- and 7beta-hydroxylated metabolites in the human brain. These 7-hydroxylated derivatives were shown to exert anti-glucocorticoid and neuroprotective effects. When these steroids are administered per os to humans, the first organ encountered is the liver, where extensive metabolism takes place. The objective of this work was to assess the cofactor dependence and metabolism of DHEA, EpiA, and their 7-hydroxylated derivatives in S9 fractions of human liver, using a radiolabeled steroid substrate for quantification and gas chromatography-mass spectrometry for identification. The best transformation yields were obtained with NADPH and were larger in female than in male. Results showed that both DHEA and EpiA mainly transformed into their 17beta-hydroxylated derivatives, 7- or 16alpha-hydroxylated metabolites under NAD(P)H conditions, and 5alpha-androstane-3,17-dione for EpiA under NAD(P)+ conditions. In turn, 7alpha-hydroxy-DHEA and 7beta-hydroxy-DHEA were partly transformed into each other via a 7-oxo-DHEA intermediate and were reduced into the 17beta-hydroxy derivative, respectively. The same type of transformations occurred for 7alpha-hydroxy-EpiA and 7beta-hydroxy-EpiA, except that no 7-oxo-EpiA intermediate was obtained. These findings determine the presence of enzymes responsible for the 7alpha- and 16alpha-hydroxylation in the human liver, the 11beta-hydroxysteroid dehydrogenase type 1 responsible for the oxidoreduction of the 7-hydroxylated substrates, and the 17beta-hydroxysteroid dehydrogenase responsible for the reduction of 17-oxo-steroids into 17beta-hydroxysteroids.