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Studies on the Origin of Circulating 18-Hydroxycortisol and 18-Oxocortisol in Normal Human Subjects

Medical Research Council Blood Pressure Group (E.M.F., L.A.S., E.C.F., E.D., R.F., J.M.C.C.), University of Glasgow, Division of Cardiovascular and Medical Sciences, Western Infirmary, Glasgow G11 6NT, Scotland, United Kingdom; and Department of Clinical Biochemistry (A.M.W.), Macewen Building, Royal Infirmary, Glasgow G4 0SF, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Robert Fraser, Medical Research Council Blood Pressure Group, Western Infirmary, Glasgow G11 6NT, Scotland, United Kingdom. E-mail: rfraser{at}clinmed.gla.ac.uk.

18-Hydroxycortisol (18-OHF) and 18-oxocortisol (18-oxoF) are derivatives of cortisol found in primary aldosteronism but whose origin and regulation in normal subjects are uncertain. 18-OHF can be synthesized by zona fasciculata 11-ß hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase (AS).

Stably transfected cell lines expressing either CYP11B1 (11ß-hydroxylase) or CYP11B2 (AS) were incubated with cortisol and other substrates over a range of concentrations. Both enzymes could synthesize 18-OHF from cortisol, but only AS could synthesize 18-oxoF. AS was more efficient than 11ß-hydroxylase at 18-hydroxylation. The apparent Michaelis-Menten constant (K_m) of AS for cortisol was estimated to be 2.6 µM.

In five patients with adrenal insufficiency maintained on hydrocortisone, urinary free cortisol and cortisone levels were high; 18-oxoF was detectable in all patients and 18-OHF in three. It is likely that the 18-oxygenated steroids were synthesized from circulating cortisol, either in the zona glomerulosa or at extraadrenal sites. In eight male volunteers, dexamethasone treatment decreased urinary excretion rates of free cortisol, cortisone, 18-OHF, and 18-oxoF, 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).

These data show, for the first time, that 18-OHF and 18-oxoF can be synthesized from circulating cortisol. The close correlation between 18-oxoF and cortisol suggests that 18-oxoF is normally produced by the action of AS using 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 11ß-hydroxylase from locally available cortisol.