11beta-hydroxysteroid dehydrogenase types 1 and 2: an important pharmacokinetic determinant for the activity of synthetic mineralo- and glucocorticoids

J Clin Endocrinol Metab. 2002 Dec;87(12):5695-701. doi: 10.1210/jc.2002-020970.


The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) system plays a pivotal role in glucocorticoid (GC) and mineralocorticoid (MC) action. Although 11beta-HSD activities are important determinants for the efficacy of synthetic MCs and GCs, corresponding pharmacokinetic data are scanty. Therefore, we characterized 11beta-HSD profiles for a wide range of steroids often used in clinical practice. 11beta-HSD1 and 11beta-HSD2 were selectively examined in 1) human liver and kidney cortex microsomes, and 2) Chinese hamster ovarian cells stably transfected with 11beta-HSD1 or 11beta-HSD2 expression vectors. Both systems produced concordant evidence for the following conclusions. Oxidation of steroids by 11beta-HSD2 is diminished if they are fluorinated in position 6alpha or 9alpha (e.g. in dexamethasone) or methylated at 2alpha or 6alpha (in methylprednisolone) or 16alpha or 16beta, by a methylene group at 16 (in prednylidene), methyloxazoline at 16, 17 (in deflazacort), or a 2-chlor configuration. Whereas the methyl groups also decrease reductase activity (steric effects), fluorination increases reductase activity (negative inductive effect), leading to a shift to reductase activity. This may explain the strong MC activity of 9alpha-fluorocortisol and should be considered in GC therapy directed to 11beta-HSD2-expressing tissues (kidney, colon, and placentofetal unit). 11beta-HSD2 oxidation of prednisolone is more effective than that of cortisol, explaining the reduced MC activity of prednisolone compared with cortisol. Reduction by 11beta-HSD1 is diminished by 16alpha-methyl, 16beta-methyl, 2alpha-methyl, and 2-chlor substitution, whereas it is increased by the Delta(1)-dehydro configuration in prednisone, resulting in higher hepatic first pass activation of prednisone compared with cortisone. To characterize a GC or a MC as substrate for the different 11betaHSDs may be essential for an optimized steroid therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • Animals
  • CHO Cells
  • Cricetinae
  • Glucocorticoids / metabolism*
  • Humans
  • Hydroxysteroid Dehydrogenases / metabolism*
  • Kidney Cortex / metabolism
  • Microsomes / metabolism
  • Microsomes, Liver / metabolism
  • Mineralocorticoids / chemical synthesis
  • Mineralocorticoids / metabolism*
  • Oxidation-Reduction
  • Substrate Specificity
  • Transfection


  • Glucocorticoids
  • Mineralocorticoids
  • Hydroxysteroid Dehydrogenases
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2
  • HSD11B1 protein, human
  • HSD11B2 protein, human