Dexamethasone and 11-dehydrodexamethasone as tools to investigate the isozymes of 11β-hydroxysteroid dehydrogenase in vitro and in vivo

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Abstract
Dexamethasone is used in the clinic to test the sensitivity of the hypothalamic–pituitary–adrenal axis to negative feedback. It has also been proposed that metabolism of dexamethasone might differentiate between the activities of the two isozymes of 11β-hydroxysteroid dehydrogenase (11 βHSD1 and 11βHSD2). We have developed a gas chromatographic mass spectrometric assay for dexamethasone and 11-dehydrodexamethasone and have confirmed in vitro that dexamethasone is a substrate for 11 β-HSD2 but not 11 β-HSD1 (conversion to 11-dehydrodexamethasone 0·6 ± 0·3% in homogenates of rat liver with NADP+ for 11β-HSD1, and 29·4 ±10·3% and 40·0 ± 2·0% in homogenates of rat and human kidney respectively with NAD+ for 11β-HSD2). However, we have also made the novel observation that 11-dehydrodexamethasone is a substrate for both isozymes (conversion to dexamethasone 65·0±20·4% for 11βHSD1 and 53·5 ± 20·8% and 69·0 ± 4·5% for 11βHSD2, rat and human respectively). In healthy humans, the concentrations of 11-dehydrodexamethasone in plasma after an intravenous bolus of dexamethasone were less than 10% of those of dexamethasone, and 11-dehydrodexamethasone was detected (at 0·8–65·0 nm) in plasma from only 11 of 20 subjects at 0900 h on the morning after oral dexamethasone (0·1–1 mg taken at 2400 h). Concentrations of 11-dehydrodexamethasone did not correlate with the degree of suppression of plasma cortisol. Thus dexamethasone is not useful in differentiating the activities of the isozymes of 11β-HSD in vivo and variations in 11β-HSD activity do not explain the interindividual variability in suppression of plasma cortisol by low doses of dexamethasone. Journal of Endocrinology (1997) 153, 41–48

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