Identification of a human blood biomarker of pharmacological
11β-hydroxysteroid dehydrogenase 1 inhibition
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.