Cortisol to cortisone: Glucocorticoid to mineralocorticoid

  • Stewart P
  • Mason J
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11β-hydroxysteroid dehydrogenase (11β-HSD), by converting cortisol and corticosterone to hormonally inactive cortisone and 11-dehydrocorticosterone, respectively, is an important pre-receptor signaling pathway for the renal mineralocorticoid receptor (MR). This receptor has an equal affinity for the glucocorticoids, cortisol and corticosterone, and for the mineralocorticoid, aldosterone. In states of 11β-HSD deficiency such as the syndrome of apparent mineralocorticoid excess (AME) and licorice ingestion, cortisol acts as a potent mineralocorticoid. In addition to the established and cloned type I 11β-HSD, a second 11β-HSD isoform has been reported in rabbit kidney and human placenta. We have analyzed the kinetics of 11β-HSD activity in human kidney and compared it with the expressed human type I 11β-HSD cDNA. Microsomes were prepared from mid-gestational human fetal kidneys and incubated with various concentrations of cortisol (0.0125-10 μM) and NAD or NADP. Kinetic analysis revealed a high affinity (apparent Km60 nM) isoform, the activity of which was exclusively NAD-dependent. No convincing NADP-dependent activity was seen. Similarly with cortisone as a substrate no 11-oxoreductase activity was evident. In contrast, when type I human 11β-HSD was ligated into the expression vector pcDNAI and transiently transfected into COS-1 cells, low affinity (apparent Km2.1 μM) NADP-dependent activity was seen. 11-Oxoreductase activity was also observed. The cloned type I human 11β-HSD encodes an enzyme with both low-affinity, NADP-dependent, dehydrogenase and 11-oxoreductase activities, but this activity is absent in human fetal kidney (and probably adult kidney). Instead, kinetic analysis reveals high affinity, NAD-dependent and unidirectional 11β-dehydrogenase activity in human kidney. We suggest that it is this novel isoform which is responsible for protecting the renal MR from glucocorticoid excess. © 1995.

Author-supplied keywords

  • cortisol
  • cortisone
  • hydroxysteroid dehydrogenase
  • kidney
  • mineralocorticoid

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  • Paul M. Stewart

  • J. Ian Mason

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