11β-Hydroxysteroid dehydrogenase activity in the brain does not contribute to systemic interconversion of cortisol and cortisone in healthy men.
OBJECTIVE
11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses regeneration of cortisol in liver, adipose tissue, and skeletal muscle, making a substantial contribution to circulating cortisol as demonstrated in humans by combining stable isotope tracer infusion with arteriovenous sampling. In the brain, 11βHSD1 is a potential therapeutic target implicated in age-associated cognitive dysfunction. We aimed to quantify brain 11βHSD1 activity, both to assess its contribution to systemic cortisol/cortisone turnover and to develop a tool for measuring 11βHSD1 in dementia and following administration of 11βHSD1 inhibitors.


METHODS
With ethical approval and informed consent, 8 healthy men aged 38.1 years (sd 16.5) underwent an ECG-gated phase-contrast magnetic resonance scan to quantify internal jugular vein blood flow and were infused with 1,2 [(2)H]2-cortisone and 9,11,12,12 [(2)H]4-cortisol for 3 h before samples were obtained from the internal jugular vein and an arterialized hand vein. Steroids were quantified by liquid chromatography-tandem mass spectrometry.


RESULTS
Steady state tracer enrichments were achieved and systemic indices of cortisol/cortisone interconversion were consistent with previous studies in healthy men. However, there was no measurable release or production of cortisol, 9,12,12 [(2)H]3-cortisol or cortisone into the internal jugular vein.


CONCLUSIONS
Although cerebral 11βHSD1 reductase activity may be greater in cognitively impaired patients, in healthy men any contribution of 11βHSD1 in the brain to systemic cortisol/cortisone turnover is negligible. The influence of 11βHSD1 in the brain is likely confined to subregions, notably the hippocampus. Alternative approaches are required to quantify pharmacodynamics effects of 11βHSD1 inhibitors in the human brain.
MRC Centre for Cognitive Aging and Cognitive Epidemiology (A.H.M.K.), Geriatric Medicine Unit, and Centre for Clinical Brain Sciences (S.S., I.M., P.A.), University of Edinburgh, Edinburgh, United Kingdom; Clinical Research Imaging Centre (S.S.) and BHF Centre for Cardiovascular Science (S.S., R.A., B.R.W.), Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; Critical Care (P.A.), Western General Hospital, NHS Lothian University Hospitals Division, Edinburgh EH4 2XU, United Kingdom.
Alixe H M
AH
Kilgour
Scott
S
Semple
Ian
I
Marshall
Peter
P
Andrews
Ruth
R
Andrew
Brian R
BR
Walker
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000328:Adult; D001921:Brain / Q000201:enzymology*; D002853:Chromatography, Liquid; D003348:Cortisone / Q000097:blood*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone; D006854:Hydrocortisone