The oxidized bile acid 7-oxoLCA (7-oxolithocholic acid), formed primarily by gut micro-organisms, is reduced in human liver to CDCA (chenodeoxycholic acid) and, to a lesser extent, UDCA (ursodeoxycholic acid). The enzyme(s) responsible remained unknown. Using human liver microsomes, we observed enhanced 7-oxoLCA reduction in the presence of detergent. The reaction was dependent on NADPH and stimulated by glucose 6-phosphate, suggesting localization of the enzyme in the ER (endoplasmic reticulum) and dependence on NADPH-generating H6PDH (hexose-6-phosphate dehydrogenase). Using recombinant human 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1), we demonstrate efficient conversion of 7-oxoLCA into CDCA and, to a lesser extent, UDCA. Unlike the reversible metabolism of glucocorticoids, 11β-HSD1 mediated solely 7-oxo reduction of 7-oxoLCA and its taurine and glycine conjugates. Furthermore, we investigated the interference of bile acids with 11β-HSD1-dependent interconversion of glucocorticoids. 7-OxoLCA and its conjugates preferentially inhibited cortisone reduction, and CDCA and its conjugates inhibited cortisol oxidation. Three-dimensional modelling provided an explanation for the binding mode and selectivity of the bile acids studied. The results reveal that 11β-HSD1 is responsible for 7-oxoLCA reduction in humans, providing a further link between hepatic glucocorticoid activation and bile acid metabolism. These findings also suggest the need for animal and clinical studies to explore whether inhibition of 11β-HSD1 to reduce cortisol levels would also lead to an accumulation of 7-oxoLCA, thereby potentially affecting bile acid-mediated functions.
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Research Article|
May 27 2011
Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1
Alex Odermatt;
Alex Odermatt
1
*Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
1To whom correspondence should be addressed (email alex.odermatt@unibas.ch).
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Thierry Da Cunha;
Thierry Da Cunha
*Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
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Carlos A. Penno;
Carlos A. Penno
*Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
†Preclinical Safety, Novartis Institute for Biomedical Research, CH-4009 Basel, Switzerland
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Charlie Chandsawangbhuwana;
Charlie Chandsawangbhuwana
‡Department of Medicine, 0693 University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, U.S.A.
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Christian Reichert;
Christian Reichert
*Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
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Armin Wolf;
Armin Wolf
†Preclinical Safety, Novartis Institute for Biomedical Research, CH-4009 Basel, Switzerland
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Min Dong;
Min Dong
†Preclinical Safety, Novartis Institute for Biomedical Research, CH-4009 Basel, Switzerland
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Michael E. Baker
Michael E. Baker
‡Department of Medicine, 0693 University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0693, U.S.A.
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Biochem J (2011) 436 (3): 621–629.
Article history
Received:
January 04 2011
Revision Received:
April 01 2011
Accepted:
April 01 2011
Accepted Manuscript online:
April 01 2011
Citation
Alex Odermatt, Thierry Da Cunha, Carlos A. Penno, Charlie Chandsawangbhuwana, Christian Reichert, Armin Wolf, Min Dong, Michael E. Baker; Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1. Biochem J 15 June 2011; 436 (3): 621–629. doi: https://doi.org/10.1042/BJ20110022
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