Dual Sites of Inhibition by Metyrapone of Human Adrenal Steroidogenesis: Correlation ofin Vivoand andin VitroStudies

Abstract

In a patient with pituitary ACTH-dependent adrenal hyperplasia (AH), the standard oral metyrapone test resulted in a decrease in "apparent 11beta-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 11beta-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 11beta-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 11beta-hydroxylase (-62%) and cholesterol cleavage (-36%) "apparent activities"; when metyrapone and ACTH were given together to this patient, however, only 11beta-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 mitochondrial reactions involved in cortisol synthesis--initial cholesterol cleavage and final 11beta-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 11beta-hydroxylation, the outcome of metyrapone administration is thus determined by whether a change in ACTH level ensues: while 11beta-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.

11β-Hydroxylase inhibitors protect against seizures in mice by increasing endogenous neurosteroid synthesis

“…Metyrapone and etomidate are known to inhibit CYP11B1, resulting in a suppression of glucocorticoid synthesis (Jenkins et al, 1958; Carballeira et al, 1976). Reduced negative feedback of the HPA axis leads to elevated ACTH, which stimulates steroidogenesis.…”

“…Because all of these neurosteroids have anticonvulsant properties (Kokate et al, 1994; Reddy and Rogawski, 2002; Kaminski et al, 2005), it is plausible that CYP11B1 inhibitors could protect against seizures. We investigated this possibility using two inhibitors of CYP11B1, metyrapone and etomidate (Carballeira et al, 1976; Dörr et al, 1984; De Coster et al, 1985; Lambert et al, 1986; Weber et al, 1993). Metyrapone is used clinically in the treatment of Cushing’s syndrome (hypercorticism).…”

Effects of the pattern of glucocorticoid replacement on neural processing, emotional reactivity and well-being in healthy male individuals: study protocol for a randomised controlled trial

“…Metyrapone was chosen to suppress endogenous cortisol production for both safety reasons (as it has a short half-life [ 17 ]) and because it does not interfere with cortisol’s molecular physiology. Metyrapone blocks cortisol synthesis by inhibiting steroid 11β-hydroxylase [ 18 ]. These three methods for creating different patterns of systemic cortisol dynamics in healthy individuals offered the basis for the temporal design of study stage 2 (see below).…”

Medical Treatment of Cushing’s Syndrome: Adrenal-Blocking Drugs and Ketaconazole

“…Metyrapone blocks the last step of cortisol synthesis by inhibition of 11β-hydroxylase [14] and can decrease cortisol production in patients with adrenal tumors, ectopic ACTH production and Cushing’s disease [15]. Effective dosages of metyrapone vary between 500 and 6,000 mg/day [1,2].…”