Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis

Details

Serval ID
serval:BIB_C60964A42B47
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis
Journal
Journal of Clinical Investigation
Author(s)
Quattropani  C., Vogt  B., Odermatt  A., Dick  B., Frey  B. M., Frey  F. J.
ISSN
0021-9738 (Print)
Publication state
Published
Issued date
11/2001
Volume
108
Number
9
Pages
1299-305
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Nov
Abstract
Enhanced renal sodium retention and potassium loss in patients with cirrhosis is due to activation of mineralocorticoid receptors (MRs). Increased aldosterone concentrations, however, do not entirely explain the activation of MR in cirrhosis. Here, we hypothesize that cortisol activates MRs in patients with cholestasis. We present evidence that access of cortisol to MRs is a result of bile acid-mediated inhibition of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2), an MR-protecting enzyme that converts cortisol to cortisone. Twelve patients with biliary obstruction and high plasma bile acid levels were studied before and after removal of the obstruction. The urinary ratio of (tetrahydrocortisol + 5 alpha-tetrahydrocortisol)/tetrahydrocortisone, a measure of 11 beta-HSD2 activity, decreased from a median of 1.91 during biliary obstruction to 0.78 at 4 and 8 weeks after removal of the obstruction and normalization of plasma bile acid concentrations. In order to demonstrate that bile acids facilitate access of cortisol to the MR by inhibiting 11 beta-HSD2, an MR translocation assay was performed in HEK-293 cells transfected with human 11 beta-HSD2 and tagged MR. Increasing concentrations of chenodeoxycholic acid led to cortisol-induced nuclear translocation of MR. In conclusion, 11 beta-HSD2 activity is reduced in cholestasis, which results in MR activation by cortisol.
Keywords
11-beta-Hydroxysteroid Dehydrogenase Type 2 11-beta-Hydroxysteroid Dehydrogenases Active Transport, Cell Nucleus Adolescent Adult Aged Aged, 80 and over Aldosterone/blood Bile Acids and Salts/blood/metabolism Cell Line Chenodeoxycholic Acid/blood/urine Cholestasis/*enzymology Dose-Response Relationship, Drug Female Fibrosis/*metabolism Gas Chromatography-Mass Spectrometry Humans Hydrocortisone/metabolism Hydroxysteroid Dehydrogenases/*metabolism/*urine Kidney/metabolism Male Microscopy, Fluorescence Middle Aged Models, Chemical Potassium/metabolism Sodium/metabolism Tetrahydrocortisol/chemistry/urine Time Factors Transfection
Pubmed
Web of science
Create date
25/01/2008 13:03
Last modification date
20/08/2019 15:41
Usage data