METYRAPONE IS A COMPETITIVE INHIBITOR OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1 REDUCTASE

The present study was designed to examine the effects of metyrapone ir t vitro on the activities of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) types 1 and 2, the two intracellular enzymes responsible for the metabolism of glucocorticoids. Enzymatic activities of 11 beta-HS D1 and 2 were determined by a radiometric conversion assay using corti sol and cortisone as physiological substrates. The enzyme activity ass ays were carried out in the absence and presence of metyrapone using s heep liver and kidney microsomes as the source of 11 beta-HSD1 and 2, respectively. It was found that metyrapone inhibited the reductase act ivity of 11 beta-HSD1 in a dose-dependent manner with an apparent K-i of 30 mu M. Moreover, this inhibition was competitive because the K, f or cortisone was increased in the presence of metyrapone. In contrast, metyrapone showed biphasic effects on the dehydrogenase activity of 1 1 beta-HSD1, in that it increased the activity at concentrations lower than 100 mu M but decreased it at higher concentrations. However, und er similar conditions, metyrapone had little effect on the unidirectio nal dehydrogenase activity of 11 beta-HSD2. In conclusion, the present results provide the first direct evidence that metyrapone is a compet itive inhibitor of 11 beta-HSD1 reductase, and that it also exerts bip hasic effects on 11 beta-HSD1 dehydrogenase activity. These findings i ndicate that metyrapone influences peripheral glucocorticoid metabolis m through its regulation of 11 beta-HSD1 activity, in addition to its classic inhibitory effects on adrenal steroid biosynthesis. It is ther efore imperative that this novel extra-adrenal effect of metyrapone be considered when this drug is used in the diagnosis and treatment of a drenocorticoid-related diseases. (C) 1997 Elsevier Science Ltd.