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Department of Medicine, University of Miami School of Medicine, and Veterans Administration Hospital Miami, Florid
Reprints: A. Carballeira, M.D., Ph.D., Research Service (151), Veterans Administration Hospital, 1201 N.W. 16th Street, Miami, Florida 33125.
In a patient with pituitary ACTH-dependent adrenal hyperplasia (AH), the standard oral metyrapone test resulted in a decrease in apparent 11β-hydroxylase activity (–48%) accompanied by an increase in apparent cholesterol cleavage activity (+318%). When incubated adrenal mitochondria from this patient were studied, metyrapone inhibited both 11β-hydroxylation of labeled 11-deoxycorticosterone and cleavage of labeled cholesterol, although at 0.1 and 1.0 mM metyrapone concentrations, depression of cholesterol cleavage (23 and 54%, respectively) was less than that of 11β-hydroxylation (62 and 84%, respectively). The inhibition of cholesterol cleavage by metyrapone (26 and 62%, at 0.1 and 1.0 mM concentrations, respectively) was also demonstrable in adrenal mitochondria from a patient with hypercorticism resulting from an ACTH-independent adrenal adenoman (AA). Metyrapone administration to AA resulted in a significant depression of both 11β-hydroxylase (–62%) and cholesterol cleavage (–36%) apparent activities; when metyrapone and ACTH were given together to this patient, however, only 11β-hydroxylase apparent activity diminished (–26%), while cholesterol cleavage apparent activity was greatly augmented (+231%), thereby simulating the results of the standard metyrapone test in AH. These data demonstrate that metyrapone inhibits both mitochondria] reactions involved in cortisol synthesis—initial cholesterol cleavage and final 11β-hydroxylation; these effects probably result from interference by this agent with the interaction between substrate and related cytochrome P · 450. Since ACTH has a major stimulatory effect on cholesterol cleavage but not on 11β-hydroxylation, the outcome of metyrapone administration is thus determined by whether a change in ACTH level ensues: while 11β-hydroxylation is inhibited by metyrapone under any circumstances, total steroid output rises when a compensatory ACTH increase overcomes metyrapone inhibition of cholesterol conversion into pregnenolone and falls when metyrapone inhibition of this reaction is unopposed.
In the present report, the following trivial names have been used: metyrapone, 2-methyl-1,2-bis (3-pyridyl)-1-propanone; cholesterol, 3β-hydroxycholest-5-ene; pregnenolone, 3β-hydroxypregn-5-en-20-one; 11-deoxycortisol, 17,21-dihydroxypregn-4-ene-3,20-dione; cortisol, 11β,17,21-trihydroxypregn-4-ene-3,20 dione; 11-deoxycorticosterone, 21-hydroxypregn-4-ene-3,20-dione, and corticosterone, 11β,21-dihydroxypregn-4-ene-3,20-dione. ACTH is the abbreviation for adrenocorticotrophie hormone.
Received August 7, 1975.
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