Dual sites of inhibition by metyrapone of human adrenal steroidogenesis: correlation of in vivo and in vitro studies.
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.
D000236:Adenoma / Q000378:metabolism; D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism*; D000308:Adrenocortical Hyperfunction / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008797:Metyrapone; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D013256:Steroids / Q000652:urine
D013256:Steroids; D002784:Cholesterol; D013250:Steroid Hydroxylases; D008797:Metyrapone