title: Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1.
abstract: 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.
authors: Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. alex.odermatt@unibas.ch
authors: Alex
authors: A
authors: Odermatt
authors: Thierry
authors: T
authors: Da Cunha
authors: Carlos A
authors: CA
authors: Penno
authors: Charlie
authors: C
authors: Chandsawangbhuwana
authors: Christian
authors: C
authors: Reichert
authors: Armin
authors: A
authors: Wolf
authors: Min
authors: M
authors: Dong
authors: Michael E
authors: ME
authors: Baker
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology; D003348:Cortisone / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007700:Kinetics; D008095:Lithocholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D011994:Recombinant Proteins; C023020:7-ketolithocholic acid; D009249:NADP; D008095:Lithocholic Acid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone; D006854:Hydrocortisone