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Identification of a human blood biomarker of pharmacological 11β-hydroxysteroid dehydrogenase 1 inhibition
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  • Cristina Gómez Castella,
  • Zerin Alimajstorovic,
  • Nantia Othonos,
  • Denise Winter,
  • Sarah White,
  • Gareth Lavery,
  • Jeremy Tomlinson,
  • Alexandra J. Sinclair,
  • Alex Odermatt
Cristina Gómez Castella
University of Basel
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Zerin Alimajstorovic
University of Birmingham
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Nantia Othonos
University of Oxford
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Denise Winter
University of Basel
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Sarah White
University of Oxford
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Gareth Lavery
Nottingham Trent University
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Jeremy Tomlinson
University of Oxford
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Alexandra J. Sinclair
University of Birmingham
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Alex Odermatt
University of Basel

Corresponding Author:[email protected]

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Abstract

Background and Purpose: 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) catalyzes the oxoreduction of cortisone to cortisol, thereby amplifying levels of active glucocorticoids. It is considered a pharmaceutical target in metabolic disease and cognitive impairments. 11β-HSD1 also converts some 7oxo-steroids to their 7β-hydroxy forms. A recent study in mice described the ratio of tauroursodeoxycholic acid (TUDCA)/tauro-7oxolithocholic acid (T7oxoLCA) as a biomarker for decreased 11β-HSD1 oxoreductase activity. The present study aimed to evaluate the equivalent bile acid ratio glycoursodeoxycholic acid (GUDCA)/glyco-7oxolithocholic acid (G7oxoLCA) as a biomarker for pharmacological 11β-HSD1 inhibition in humans and compare it with the currently applied urinary (5α-tetrahydrocortisol+tetrahydrocortisol)/tetrahydrocortisone ((5αTHF+THF)/THE) ratio. Experimental Approach: Bile acid profiles were analyzed by ultra-HPLC tandem-MS in blood samples from two independent, double-blind placebo-controlled clinical studies on the orally administered selective 11β-HSD1 inhibitor AZD4017. The blood GUDCA/G7oxoLCA ratio was compared with the urinary tetrahydro-glucocorticoid ratio for the ability to detect 11β-HSD1 inhibition. Key Results: No significant alterations were observed in the bile acid profiles following 11β-HSD1 inhibition by AZD4017, except for an increase of the secondary bile acid G7oxoLCA. The enzyme product/substrate ratio GUDCA/G7oxoLCA was found to be more reliable to detect 11β-HSD1 inhibition than the absolute G7oxoLCA concentration in both cohorts. Comparison of the blood GUDCA/G7oxoLCA ratio with the urinary (5αTHF+THF)/THE ratio revealed that both ratios successfully detect 11β-HSD1 inhibition. Conclusion and Implications: 11β-HSD1 inhibition does not cause major alterations in bile acid homeostasis. The GUDCA/G7oxoLCA ratio represents the first blood biomarker of pharmacological 11β-HSD1 inhibition and may replace or complement the urinary (5αTHF+THF)/THE ratio biomarker.
20 Apr 2023Submitted to British Journal of Pharmacology
20 Apr 2023Submission Checks Completed
20 Apr 2023Assigned to Editor
20 Apr 2023Review(s) Completed, Editorial Evaluation Pending
24 Apr 2023Reviewer(s) Assigned
23 May 2023Editorial Decision: Revise Minor
16 Aug 20231st Revision Received
17 Aug 2023Submission Checks Completed
17 Aug 2023Assigned to Editor
17 Aug 2023Review(s) Completed, Editorial Evaluation Pending
28 Aug 2023Reviewer(s) Assigned
12 Sep 2023Editorial Decision: Accept