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.[1]References
- Effects of 18-hydroxylated steroids on corticosteroid production by human aldosterone synthase and 11beta-hydroxylase. Fisher, A., Friel, E.C., Bernhardt, R., Gomez-Sanchez, C., Connell, J.M., Fraser, R., Davies, E. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
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