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Drug Metabolism and Disposition Fast Forward
First published on January 13, 2005; DOI: 10.1124/dmd.104.003004

0090-9556/05/3304-563-569$20.00
DMD 33:563-569, 2005

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HUMAN LIVER S9 FRACTIONS: METABOLISM OF DEHYDROEPIANDROSTERONE, EPIANDROSTERONE, AND RELATED 7-HYDROXYLATED DERIVATIVES

Sonia Chalbot, and Robert Morfin

Laboratoire de Biotechnologie, Conservatoire National des Arts et Métiers, Paris, France

Dehydroepiandrosterone (DHEA) and 3ß-hydroxy-5{alpha}-androstan-17-one (epiandrosterone, EpiA) are both precursors for 7{alpha}- and 7ß-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 17ß-hydroxylated derivatives, 7- or 16{alpha}-hydroxylated metabolites under NAD(P)H conditions, and 5{alpha}-androstane-3,17-dione for EpiA under NAD(P)+ conditions. In turn, 7{alpha}-hydroxy-DHEA and 7ß-hydroxy-DHEA were partly transformed into each other via a 7-oxo-DHEA intermediate and were reduced into the 17ß-hydroxy derivative, respectively. The same type of transformations occurred for 7{alpha}-hydroxy-EpiA and 7ß-hydroxy-EpiA, except that no 7-oxo-EpiA intermediate was obtained. These findings determine the presence of enzymes responsible for the 7{alpha}- and 16{alpha}-hydroxylation in the human liver, the 11ß-hydroxysteroid dehydrogenase type 1 responsible for the oxidoreduction of the 7-hydroxylated substrates, and the 17ß-hydroxysteroid dehydrogenase responsible for the reduction of 17-oxo-steroids into 17ß-hydroxysteroids.

Address correspondence to: Professor Robert Morfin, Biotechnologie CNAM, 2 rue Conté, 75003 Paris, France. E-mail: morfin{at}cnam.fr




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K. Kohalmy, V. Tamasi, L. Kobori, E. Sarvary, J.-M. Pascussi, P. Porrogi, D. Rozman, R. A. Prough, U. A. Meyer, and K. Monostory
Dehydroepiandrosterone Induces Human CYP2B6 through the Constitutive Androstane Receptor
Drug Metab. Dispos., September 1, 2007; 35(9): 1495 - 1501.
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