Received for publication November 15, 2004.
Revised January 11, 2005.
Accepted for publication January 11, 2005.

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

Abstract

Dehydroepiandrosterone (DHEA) and 3-hydroxy-5-androstan-17-one (epiandrosterone, EpiA) are both precursors for 7- and 7-hydroxylated metabolites in the human brain. These 7-hydroxylated derivatives were shown to exert anti-glucocorticoid and neuroprotective effects. In the case where 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 dependency and metabolism of DHEA, EpiA, and their 7-hydroxylated derivatives in S9 fractions of human liver using a radio-labeled steroid substrate for quantification and gas-chromatography/mass spectrometry for identification. The best transformation yields were obtained with NADPH which were larger in female than in male. Results showed that both DHEA and EpiA mainly transformed into: their 17-hydroxylated derivatives; 7- or 16-hydroxylated metabolites under NAD(P)H conditions; and 5-androstane-3,17-dione for EpiA under NAD(P)⁺ conditions. In turn, 7-hydroxy-DHEA and 7-hydroxy-DHEA were partly transformed into each other via a 7-oxo-DHEA intermediate, and were reduced into the 17-hydroxy derivative, respectively. The same type of transformations occurred for 7-hydroxy-EpiA and 7-hydroxy-EpiA, except that no 7-oxo-EpiA intermediate was obtained. These findings determine the presence of enzymes responsible for the 7- and 16-hydroxylation in the human liver; the 11-hydroxysteroid dehydrogenase type 1 responsible for the oxidoreduction of the 7-hydroxylated substrates; and the 17-hydroxysteroid dehydrogenase responsible for the reduction of 17-oxo-steroids into 17-hydroxysteroids.

Key words: cytochrome P450 function, drug targeting, drug transport, endocrine regulation, gas chromatography, mass spectrometry, metabolite indentification, steroids

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