Hexose-6-phosphate dehydrogenase modulates 11beta-hydroxysteroid dehydrogenase type 1-dependent metabolism of 7-keto- and 7beta-hydroxy-neurosteroids

PLoS One. 2007 Jun 27;2(6):e561. doi: 10.1371/journal.pone.0000561.


Background: The role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in the regulation of energy metabolism and immune system by locally reactivating glucocorticoids has been extensively studied. Experiments determining initial rates of enzyme activity revealed that 11beta-HSD1 can catalyze both the reductase and the dehydrogenase reaction in cell lysates, whereas it predominantly catalyzes the reduction of cortisone to cortisol in intact cells that also express hexose-6-phosphate dehydrogenase (H6PDH), which provides cofactor NADPH. Besides its role in glucocorticoid metabolism, there is evidence that 11beta-HSD1 is involved in the metabolism of 7-keto- and 7-hydroxy-steroids; however the impact of H6PDH on this alternative function of 11beta-HSD1 has not been assessed.

Methodology: We investigated the 11beta-HSD1-dependent metabolism of the neurosteroids 7-keto-, 7alpha-hydroxy- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) and 7-keto- and 7beta-hydroxy-pregnenolone, respectively, in the absence or presence of H6PDH in intact cells. 3D-structural modeling was applied to study the binding of ligands in 11beta-HSD1.

Principal findings: We demonstrated that 11beta-HSD1 functions in a reversible way and efficiently catalyzed the interconversion of these 7-keto- and 7-hydroxy-neurosteroids in intact cells. In the presence of H6PDH, 11beta-HSD1 predominantly converted 7-keto-DHEA and 7-ketopregnenolone into their corresponding 7beta-hydroxy metabolites, indicating a role for H6PDH and 11beta-HSD1 in the local generation of 7beta-hydroxy-neurosteroids. 3D-structural modeling offered an explanation for the preferred formation of 7beta-hydroxy-neurosteroids.

Conclusions: Our results from experiments determining the steady state concentrations of glucocorticoids or 7-oxygenated neurosteroids suggested that the equilibrium between cortisone and cortisol and between 7-keto- and 7-hydroxy-neurosteroids is regulated by 11beta-HSD1 and greatly depends on the coexpression with H6PDH. Thus, the impact of H6PDH on 11beta-HSD1 activity has to be considered for understanding both glucocorticoid and neurosteroid action in different tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / chemistry
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Carbohydrate Dehydrogenases / metabolism*
  • Cells, Cultured
  • Cortisone / metabolism
  • Dehydroepiandrosterone / chemistry
  • Dehydroepiandrosterone / metabolism*
  • Humans
  • Hydrocortisone / metabolism
  • Kidney / cytology
  • Kidney / metabolism
  • Models, Molecular
  • Neurotransmitter Agents / chemistry
  • Neurotransmitter Agents / metabolism*
  • Substrate Specificity


  • Neurotransmitter Agents
  • Dehydroepiandrosterone
  • Carbohydrate Dehydrogenases
  • galactose-6-phosphate dehydrogenase
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • HSD11B1 protein, human
  • Cortisone
  • Hydrocortisone