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Endocrine Abstracts (2018) 59 P037 | DOI: 10.1530/endoabs.59.P037

SFEBES2018 Poster Presentations Adrenal and steroids (38 abstracts)

Time-dependent cortisol turnover in tissues using stable isotope tracers and MALDI Mass Spectrometry (MS) sampling

Shazia Khan 1 , Diego F Cobice 1 , Dawn EW Livingstone 1 , C Logan Mackay 2 , Scott P Webster 1 , Brian R Walker 1 & Ruth Andrew 1

1Queen’s Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK, 2SIRCAMS, School of Chemistry, University of Edinburgh, Edinburgh, UK.

Excess action of glucocorticoid hormones is implicated in metabolic disease and cognitive decline, 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) catalysing generation of active glucocorticoid hormones in tissues. The penetration rates and tissue-specific contribution of 11βHSD1 to glucocorticoid turnover were assessed using tracer kinetics. 9,11,12,12-d4-Cortisol (d4F) was infused (1.75 mg/day, 7 days) into C57Bl6/J male mice and mice lacking 11βHSD1 (n=3/group). Regeneration of d3F by 11βHSD1-mediated reduction was assessed in plasma by LC-MS/MS and in tissues using matrix assisted laser desorption ionisation (MALDI) MS. Mean±SEM. Circulating concentrations of d4F were 936±45 nM at 24 h, reducing to 566±63 nM at 48 h, and remaining steady until 7days, suggesting an initial stimulation of clearance (or changes in infusion rate). This pattern was mirrored in liver; d4F was detected at 6 h, increasing to 24 h and then plateaued at a lower level (~75% of 24 h) by 48 h. d4F was detectable in brain by 6 h, reaching steady state by 24 h, 3.5 fold lower than liver. Tracer was not detected in adipose until 24 h, remaining steady (4 fold lower than liver) until 7 days. D3F was detected in plasma, liver and brain at 6 h, but only after 48 h in adipose. Again in plasma and liver the amounts of d3F peaked at 24 h and declined to steady state at 48 h. D3F abundance in adipose and brain did not change from 24 h to 7days. Regeneration of d3F was abolished in mice lacking 11βHSD1, without changing circulating or tissue levels of d4F. Glucocorticoid regeneration of d3F is mediated solely by 11βHSD1 and circulating levels largely mirror hepatic production. Less glucocorticoid is regenerated in brain and adipose and levels are less dependent of the circulating pool, demonstrating the important contribution of the local enzyme and the importance of targeting therapies to specific tissues, such as brain.

Volume 59

Society for Endocrinology BES 2018

Glasgow, UK
19 Nov 2018 - 21 Nov 2018

Society for Endocrinology 

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