The origin of circulating 18-oxo and 18-hydroxycortisol in normal human subjects

Freel, E.M., Shakerdi, L., Friel, E., Wallace, A.M., Davies, E. , Fraser, R. and Connell, J.M.C. (2004) The origin of circulating 18-oxo and 18-hydroxycortisol in normal human subjects. Journal of Clinical Endocrinology and Metabolism, 89(9), pp. 4628-4633. (doi: 10.1210/jc.2004-0379)

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18-hydroxycortisol (18-OHF) and 18-oxocortisol (18oxo-F) are derivatives of cortisol found in Primary Aldosteronism but whose origin and regulation in normal subjects is uncertain. 18-OHF can be synthesised by zona fasciculata 11-β hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase (AS). Stably transfected cell lines expressing either CYP11B1 (11β-hydroxylase) or CYP11B2 (AS) were incubated with cortisol and other substrates over a range of concentrations. Both enzymes could synthesise 18-OHF from cortisol but only AS could synthesise 18-oxoF. AS was more efficient than 11β-hydroxylase at 18-hydroxylation. The apparent Km of AS for cortisol was estimated to be 2.6μM. In 5 patients with adrenal insufficiency maintained on hydrocortisone, urinary free cortisol and cortisone levels were high; 18-oxoF was detectable in all patients and 18-hydroxycortisol in 3. It is likely that the 18-oxygenated steroids were synthesised from circulating cortisol, either in the zona glomerulosa or at extra-adrenal sites. In 8 male volunteers, dexamethasone treatment decreased urinary excretion rates of free cortisol, cortisone, 18-OHF and 18-oxoFl, confirming dependence of 18-oxygenated steroid levels on cortisol availability. In both groups, hydrocortisone administration resulted in detectable levels of 18-OHF and raised levels of 18-oxoF. There was close correlation between 18-oxoF and cortisol excretion during hydrocortisone administration in normal subjects (r=0.86, p<0.001).<p></p> These data show, for the first time, that 18-OHF and 18oxoF can be synthesised from circulating cortisol. The close correlation between 18-oxoF and cortisol suggests that 18-oxoF is normally produced by the action of aldosterone synthase utilising circulating cortisol as a substrate. Although 18OHF can be synthesized using circulating cortisol as substrate, our data suggest this is normally produced in the zona fasciculata by 11β-hydroxylase from locally available cortisol.<p></p>

Item Type:Articles
Glasgow Author(s) Enlighten ID:Davies, Professor Eleanor and Connell, Professor John and Freel, Dr Marie and Friel, Mrs Elaine
Authors: Freel, E.M., Shakerdi, L., Friel, E., Wallace, A.M., Davies, E., Fraser, R., and Connell, J.M.C.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Journal of Clinical Endocrinology and Metabolism
ISSN (Online):1945-7197

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