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Effects of 18-Hydroxylated Steroids on Corticosteroid Production by Human Aldosterone Synthase and 11ß-Hydroxylase

Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics (A.F., E.C.F., J.M.C.C., R.F., E.D.), Western Infirmary, Glasgow, Scotland G11 6NT; Department of Biochemistry, Universität des Saarlandes (R.B.), D-66041 Saarbrucken, Germany; and University of Mississippi Medical Center and the G. V. (Sonny) Montgomery Veterans Affairs Hospital (C.G.-S.), Jackson, Mississippi 39216

Address all correspondence and requests for reprints to: Prof. R. Fraser, Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland G11 6NT. E-mail: rfraser{at}clinmed.gla.ac.uk

Abstract

In glucocorticoid-suppressible hyperaldosteronism, 11ß- hydroxylase activity is impaired. A chimeric enzyme formed from the control elements of 11ß-hydroxylase and the structural elements of aldosterone synthase is expressed ectopically in the zona fasciculata, thus exposing cortisol to aldosterone synthase. Increased quantities of 18-hydroxycortisol and 18-oxocortisol are synthesized, which, it has been suggested, might have a local inhibitory effect on the normal 11ß-hydroxylase. The effects of these compounds and also of 18-hydroxydeoxycorticosterone were tested in cells stably transfected with CYP11B1 and CYP11B2, the genes encoding 11ß-hydroxylase and aldosterone synthase, respectively. Neither 18-hydroxycortisol nor 18-oxocortisol affected the efficiency of use of 11-deoxycorticosterone or 11-deoxycortisol as substrates by the enzymes. 18-Hydroxydeoxycorticosterone significantly reduced the conversion rate of 11-deoxycorticosterone to corticosterone and that of 11-deoxycortisol to cortisol by both enzymes, but the production rate of 18- hydroxycorticosterone and aldosterone by aldosterone synthase increased. Aldosterone synthase was able to convert 18-hydroxydeoxycorticosterone to 18-hydroxycorticosterone and aldosterone, although its affinity for this substrate was lower (4.76 µmol/liter) than that for 11-deoxycorticosterone (0.11 µmol/liter). 11ß-Hydroxylase was unable to convert 18- hydroxydeoxycorticosterone to 18-hydroxycorticosterone. 18-Hydroxycortisol and 18-oxocortisol are not, therefore, the cause of lower 11ß-hydroxylase activity in glucocorticoid- suppressible hyperaldosteronism. 18-Hydroxydeoxycorticosterone can be converted to aldosterone, but its local concentration in man and its K_m suggest that it is unlikely to be important.

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