Effects of 18-hydroxylated steroids on corticosteroid production by human aldosterone synthase and 11beta-hydroxylase.
In glucocorticoid-suppressible hyperaldosteronism, 11beta- hydroxylase activity is impaired. A chimeric enzyme formed from the control elements of 11beta-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 11beta-hydroxylase. The effects of these compounds and also of 18-hydroxydeoxycorticosterone were tested in cells stably transfected with CYP11B1 and CYP11B2, the genes encoding 11beta-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 micromol/liter) than that for 11-deoxycorticosterone (0.11 micromol/liter). 11beta-Hydroxylase was unable to convert 18- hydroxydeoxycorticosterone to 18-hydroxycorticosterone. 18-Hydroxycortisol and 18-oxocortisol are not, therefore, the cause of lower 11beta-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.
Fisher
A
A
Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland G11 6NT.
Friel
E C
EC
Bernhardt
R
R
Gomez-Sanchez
C
C
Connell
J M
JM
Fraser
R
R
Davies
E
E
D000305:Adrenal Cortex Hormones / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D019405:Cytochrome P-450 CYP11B2 / Q000378:metabolism*; D006801:Humans; D006914:Hydroxysteroids / Q000494:pharmacology*; D007700:Kinetics; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism*
D000305:Adrenal Cortex Hormones; D006914:Hydroxysteroids; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase