Metyrapone is a competitive inhibitor of 11β-hydroxysteroid dehydrogenase type 1 reductase

• Published in: Journal of Steroid Biochemistry and Molecular Biology Vol. 62; no. 2; pp. 195 - 199
• Main Authors: Sampath-Kumar, R., Yu, M., Khalil, M.W., Yang, K.
• Format: Book Review Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.06.1997; Elsevier Science
• Subjects: Biological and medical sciences; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Enzyme; Toxicity; Liver; Metyrapone; Enzyme inhibitor; Competitive inhibition; Kidney; Vertebrata; Mammalia; Animal; 11β-Hydroxysteroid dehydrogenase; Sheep; Artiodactyla; Oxidoreductases; Ungulata; Reductase
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/S0960-0760(97)00027-7

The present study was designed to examine the effects of metyrapone in vitro on the activities of 11β-hydroxysteroid dehydrogenase (11β-HSD) types 1 and 2, the two intracellular enzymes responsible for the metabolism of glucocorticoids. Enzymatic activities of 11β-HSD1 and 2 were determined by a radiometric conversion assay using cortisol and cortisone as physiological substrates. The enzyme activity assays were carried out in the absence and presence of metyrapone using sheep liver and kidney microsomes as the source of 11β-HSD1 and 2, respectively. It was found that metyrapone inhibited the reductase activity of 11β-HSD1 in a dose-dependent manner with an apparent K i of 30 μM. Moreover, this inhibition was competitive because the K m for cortisone was increased in the presence of metyrapone. In contrast, metyrapone showed biphasic effects on the dehydrogenase activity of 11β-HSD1, in that it increased the activity at concentrations lower than 100 μM but decreased it at higher concentrations. However, under similar conditions, metyrapone had little effect on the unidirectional dehydrogenase activity of 11β-HSD2. In conclusion, the present results provide the first direct evidence that metyrapone is a competitive inhibitor of 11β-HSD1 reductase, and that it also exerts biphasic effects on 11β-HSD1 dehydrogenase activity. These findings indicate that metyrapone influences peripheral glucocorticoid metabolism through its regulation of 11β-HSD1 activity, in addition to its classic inhibitory effects on adrenal steroid biosynthesis. It is therefore imperative that this novel extra-adrenal effect of metyrapone be considered when this drug is used in the diagnosis and treatment of adrenocorticoid-related diseases.