Non-invasive in Vivo Assessment of 11β-hydroxysteroid Dehydrogenase Type 1 Activity by F-Magnetic Resonance Spectroscopy

Overview

Journal Sci Rep

Specialty Science

Date 2022 Sep 29

PMID 36175417

Authors

Gregorio Naredo-Gonzalez

Rita Upreti

Maurits A Jansen

Scott Semple

Oliver B Sutcliffe

Ian Marshall

Brian R Walker

Ruth Andrew

Affiliations

Soon will be listed here.

Abstract

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels and is a pharmaceutical target in diabetes and cognitive decline. Clinical translation of inhibitors is hampered by lack of in vivo pharmacodynamic biomarkers. Our goal was to monitor substrates and products of 11β-HSD1 non-invasively in liver via Fluorine magnetic resonance spectroscopy (F-MRS). Interconversion of mono/poly-fluorinated substrate/product pairs was studied in Wistar rats (male, n = 6) and healthy men (n = 3) using 7T and 3T MRI scanners, respectively. Here we show that the in vitro limit of detection, as absolute fluorine content, was 0.625 μmole in blood. Mono-fluorinated steroids, dexamethasone and 11-dehydrodexamethasone, were detected in phantoms but not in vivo in human liver following oral dosing. A non-steroidal polyfluorinated tracer, 2-(phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethanone and its metabolic product were detected in vivo in rat liver after oral administration of the keto-substrate, reading out reductase activity. Administration of a selective 11β-HSD1 inhibitor in vivo in rats altered total liver F-MRS signal. We conclude that there is insufficient sensitivity to measure mono-fluorinated tracers in vivo in man with current dosage regimens and clinical scanners. However, since reductase activity was observed in rats using poly-fluorinated tracers, this concept could be pursued for translation to man with further development.

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References

van Laarhoven H, Klomp D, Rijpkema M, Kamm Y, Wagener D, Barentsz J . Prediction of chemotherapeutic response of colorectal liver metastases with dynamic gadolinium-DTPA-enhanced MRI and localized 19F MRS pharmacokinetic studies of 5-fluorouracil. NMR Biomed. 2006; 20(2):128-40. DOI: 10.1002/nbm.1098. View

Klomp D, van Laarhoven H, Scheenen T, Kamm Y, Heerschap A . Quantitative 19F MR spectroscopy at 3 T to detect heterogeneous capecitabine metabolism in human liver. NMR Biomed. 2006; 20(5):485-92. DOI: 10.1002/nbm.1111. View

Andrew R, Westerbacka J, Wahren J, Yki-Jarvinen H, Walker B . The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. Diabetes. 2005; 54(5):1364-70. DOI: 10.2337/diabetes.54.5.1364. View

Webster S, Ward P, Binnie M, Craigie E, McConnell K, Sooy K . Discovery and biological evaluation of adamantyl amide 11beta-HSD1 inhibitors. Bioorg Med Chem Lett. 2007; 17(10):2838-43. DOI: 10.1016/j.bmcl.2007.02.057. View

van Laarhoven H, Klomp D, Kamm Y, Punt C, Heerschap A . In vivo monitoring of capecitabine metabolism in human liver by 19fluorine magnetic resonance spectroscopy at 1.5 and 3 Tesla field strength. Cancer Res. 2003; 63(22):7609-12. View

Hult M, Nobel C, Abrahmsen L, Jornvall H, Oppermann U . Novel enzymological profiles of human 11beta-hydroxysteroid dehydrogenase type 1. Chem Biol Interact. 2001; 130-132(1-3):805-14. DOI: 10.1016/s0009-2797(00)00236-2. View

Klomp D, van Laarhoven H, Kentgens A, Heerschap A . Optimization of localized 19F magnetic resonance spectroscopy for the detection of fluorinated drugs in the human liver. Magn Reson Med. 2003; 50(2):303-8. DOI: 10.1002/mrm.10527. View

Saether O, Risa O, cejkova J, Krane J, Midelfart A . High-resolution magic angle spinning 1H NMR spectroscopy of metabolic changes in rabbit lens after treatment with dexamethasone combined with UVB exposure. Graefes Arch Clin Exp Ophthalmol. 2004; 242(12):1000-7. DOI: 10.1007/s00417-004-1030-8. View

Courtney R, Stewart P, Toh M, Ndongo M, Calle R, Hirshberg B . Modulation of 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity biomarkers and pharmacokinetics of PF-00915275, a selective 11betaHSD1 inhibitor. J Clin Endocrinol Metab. 2007; 93(2):550-6. DOI: 10.1210/jc.2007-1912. View

10.

Kotelevtsev Y, Holmes M, Burchell A, Houston P, Schmoll D, Jamieson P . 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A. 1998; 94(26):14924-9. PMC: 25139. DOI: 10.1073/pnas.94.26.14924. View

11.

Finckh C, Atalla A, Nagel G, Stinner B, Maser E . Expression and NNK reducing activities of carbonyl reductase and 11beta-hydroxysteroid dehydrogenase type 1 in human lung. Chem Biol Interact. 2001; 130-132(1-3):761-73. DOI: 10.1016/s0009-2797(00)00306-9. View

12.

Rosenstock J, Banarer S, Fonseca V, Inzucchi S, Sun W, Yao W . The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care. 2010; 33(7):1516-22. PMC: 2890352. DOI: 10.2337/dc09-2315. View

13.

Befroy D, Shulman G . Magnetic resonance spectroscopy studies of human metabolism. Diabetes. 2011; 60(5):1361-9. PMC: 3292308. DOI: 10.2337/db09-0916. View

14.

Henry M, Moore C, Kaufman M, Michelson D, Schmidt M, Stoddard E . Brain kinetics of paroxetine and fluoxetine on the third day of placebo substitution: a fluorine MRS study. Am J Psychiatry. 2000; 157(9):1506-8. DOI: 10.1176/appi.ajp.157.9.1506. View

15.

van Gorp J, Seevinck P, Andreychenko A, Raaijmakers A, Luijten P, Viergever M . (19)F MRSI of capecitabine in the liver at 7 T using broadband transmit-receive antennas and dual-band RF pulses. NMR Biomed. 2015; 28(11):1433-42. DOI: 10.1002/nbm.3390. View

16.

Hermanowski-Vosatka A, Balkovec J, Cheng K, Chen H, Hernandez M, Koo G . 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 2005; 202(4):517-27. PMC: 2212859. DOI: 10.1084/jem.20050119. View

17.

Rask E, Olsson T, Soderberg S, Andrew R, Livingstone D, Johnson O . Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001; 86(3):1418-21. DOI: 10.1210/jcem.86.3.7453. View

18.

Sooy K, Noble J, McBride A, Binnie M, Yau J, Seckl J . Cognitive and Disease-Modifying Effects of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer's Disease. Endocrinology. 2015; 156(12):4592-603. PMC: 4655221. DOI: 10.1210/en.2015-1395. View

19.

Midelfart A, Dybdahl A, Muller N, Sitter B, Gribbestad I, Krane J . Dexamethasone and dexamethasone phosphate detected by 1H and 19F NMR spectroscopy in the aqueous humour. Exp Eye Res. 1998; 66(3):327-37. DOI: 10.1006/exer.1997.0429. View

20.

Best R, Nelson S, Walker B . Dexamethasone and 11-dehydrodexamethasone as tools to investigate the isozymes of 11 beta-hydroxysteroid dehydrogenase in vitro and in vivo. J Endocrinol. 1997; 153(1):41-8. DOI: 10.1677/joe.0.1530041. View