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\begin{document}

\title{Identification of a human blood biomarker of pharmacological
11\selectlanguage{greek}β-\selectlanguage{english}hydroxysteroid dehydrogenase 1 inhibition\selectlanguage{english}}



\author[1]{Cristina Gómez Castella}%
\author[2]{Zerin Alimajstorovic}%
\author[3]{Nantia Othonos}%
\author[1]{Denise Winter}%
\author[3]{Sarah White}%
\author[4]{Gareth Lavery}%
\author[3]{Jeremy Tomlinson}%
\author[2]{Alexandra J. Sinclair}%
\author[1]{Alex Odermatt}%
\affil[1]{University of Basel}%
\affil[2]{University of Birmingham}%
\affil[3]{University of Oxford}%
\affil[4]{Nottingham Trent University}%


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  \date{May 20, 2024}


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\begin{abstract}
Background and Purpose: 11\selectlanguage{greek}β-\selectlanguage{english}hydroxysteroid dehydrogenase 1 (11\selectlanguage{greek}β-\selectlanguage{english}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. 11\selectlanguage{greek}β-\selectlanguage{english}HSD1 also
converts some 7oxo-steroids to their 7\selectlanguage{greek}β-\selectlanguage{english}hydroxy forms. A recent study in
mice described the ratio of tauroursodeoxycholic acid
(TUDCA)/tauro-7oxolithocholic acid (T7oxoLCA) as a biomarker for
decreased 11\selectlanguage{greek}β-\selectlanguage{english}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 11\selectlanguage{greek}β-\selectlanguage{english}HSD1 inhibition in humans and compare it with the
currently applied urinary
(5\selectlanguage{greek}α-\selectlanguage{english}tetrahydrocortisol+tetrahydrocortisol)/tetrahydrocortisone
((5\selectlanguage{greek}α\selectlanguage{english}THF+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 11\selectlanguage{greek}β-\selectlanguage{english}HSD1 inhibitor AZD4017. The blood
GUDCA/G7oxoLCA ratio was compared with the urinary
tetrahydro-glucocorticoid ratio for the ability to detect 11\selectlanguage{greek}β-\selectlanguage{english}HSD1
inhibition. Key Results: No significant alterations were observed in the
bile acid profiles following 11\selectlanguage{greek}β-\selectlanguage{english}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 11\selectlanguage{greek}β-\selectlanguage{english}HSD1 inhibition than the absolute G7oxoLCA concentration in
both cohorts. Comparison of the blood GUDCA/G7oxoLCA ratio with the
urinary (5\selectlanguage{greek}α\selectlanguage{english}THF+THF)/THE ratio revealed that both ratios successfully
detect 11\selectlanguage{greek}β-\selectlanguage{english}HSD1 inhibition. Conclusion and Implications: 11\selectlanguage{greek}β-\selectlanguage{english}HSD1
inhibition does not cause major alterations in bile acid homeostasis.
The GUDCA/G7oxoLCA ratio represents the first blood biomarker of
pharmacological 11\selectlanguage{greek}β-\selectlanguage{english}HSD1 inhibition and may replace or complement the
urinary (5\selectlanguage{greek}α\selectlanguage{english}THF+THF)/THE ratio biomarker.%
\end{abstract}%



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