Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroepiandrosterone: A role for 11β-hydroxysteroid dehydrogenases?

Boaz Robinzon, Kristy K. Michael, Sharon L. Ripp, Stephen J. Winters, Russell A. Prough*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

The cytochrome P450-dependent formation and subsequent interconversion of dehydroepiandrosterone (DHEA) metabolites 7α-hydroxy-DHEA (7α-OH-DHEA), 7β-hydroxy-DHEA (7β-OH-DHEA), and 7-oxo-DHEA was observed in human, pig, and rat liver microsomal fractions. Rat liver mitochondria and nuclei also converted DHEA to 7α-OH-DHEA and 7-oxo-DHEA, but at a lower rate. With NADP+, and less so with NAD+, rat, pig, and human liver microsomes and rat liver mitochondria and nuclei converted 7α-OH-DHEA to 7-oxo-DHEA. This reaction was inhibited by corticosterone and the 11β-hydroxysteroid dehydrogenase (11βHSD) inhibitor carbenoxolone (CBX). The conversion of 7α-OH-DHEA to 7-oxo-DHEA by rat kidney occurred at higher rates with NAD+ than with NADP+ and was inhibited by corticosterone. With NADPH, 7-oxo-DHEA was converted to unidentified hydroxylated metabolites and low levels of 7α-OH-DHEA by rat liver microsomes. In contrast, pig liver microsomal fractions reduced 7-oxo-DHEA to nearly equal amounts of 7α- and 7β-OH-DHEA, while human fractions produced mainly 7β-OH-DHEA. Dehydrocorticosterone inhibited the reduction to both isomers by pig liver microsomes, but only to 7α-OH-DHEA by human microsomes; CBX inhibited both reactions. Rat kidney did not reduce 7-oxo-DHEA with either NADPH or NADH. These results demonstrate that DHEA is first converted in liver to 7α-OH-DHEA, which is subsequently oxidized to 7-oxo-DHEA in both liver and kidney. In liver, interconversion of 7-oxo-DHEA and 7-OH-DHEA isomers is largely catalyzed by 11βHSD1, while in kidney 11βHSD2 (NAD+-dependent) and 11βHSD3 (NADP+-dependent) likely catalyze the unidirectional oxidation of 7α-hydroxy-DHEA to 7-oxo-DHEA. Distinct species-specific routes of metabolism of DHEA and the interconversion of its metabolites obviate extrapolation of animal studies to humans.

Original languageEnglish
Pages (from-to)251-258
Number of pages8
JournalArchives of Biochemistry and Biophysics
Volume412
Issue number2
DOIs
StatePublished - 15 Apr 2003

Keywords

  • 11β-Hydroxysteroid dehydrogenase
  • 7-Oxo-DHEA
  • 7α-Hydroxy-DHEA
  • 7β-Hydroxy-DHEA
  • Brain
  • Corticosterone
  • Dehydrocorticosterone
  • Dehydroepiandrosterone
  • Humans
  • Kidney
  • Liver
  • Pig
  • Rats

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