Parallelism of 11 beta- and 18-hydroxylation demonstrated by urinary free hormones in man

To investigate whether the functions of 11 beta- and 18-hydroxylase are parallel in the human adrenal cortex, we measured urinary free deoxycorticosterone (DOC), free 18-hydroxy-DOC (18-OH-DOC), and free corticosterone (B) in 22 subjects (aged 3 6/12 to 19 yr) before and after metyrapone administration and ACTH infusion. The substrate to product ratio was used as an index of enzyme activity. There were parallel changes in the ratios of DOC to B (11 beta-hydroxylase) and DOC to 18-OH-DOC (18-hydroxylase) in all conditions, while the B to 18-OH-DOC ratio (product ratio) was relatively constant. The correlations between the ratios of DOC to B and DOC to 18-OH-DOC as well as between B and 18-OH-DOC were highly significant under all conditions (r = 0.89; P = 0.00001). These findings are consistent with previous in vitro studies and studies in patients with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency, suggesting that a single enzyme system is responsible for both 11 beta- and 18-hydroxylation of DOC in the adrenal zona fasciculata. As part of the metyrapone study, 18-OH-B was measured: 18-OH-B values decreased significantly, and the B to 18-OH-B ratio increased during metyrapone administration (from 0.38 +/- 0.09 to 1.79 +/- 0.04; P < 0.005), showing inhibition of 18-hydroxylation of B as well. Since 18-OH-B was suppressed without a decrease in PRA, we concluded that this inhibition is a primary metyrapone effect and not the result of increased DOC and suppressed PRA.