Molecular analysis of 11β-hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess

Perrin C. White, Tomoatsu Mune, Fraser M. Rogerson, Kathleen M. Kayes, Anil K. Agarwal

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11β-hydroxysteroid dehydrogenase (11-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. The deficiency allows mineralocorticoid receptors to be occupied by cortisol, because these receptors themselves have similar affinities for cortisol and aldosterone. There are two isozymes of 11-HSD, a liver (L) or type 1 isozyme with a relatively low affinity for steroids, and a kidney (K) or type 2 isozyme with high steroid affinity. Mutations in the gene for the kidney isozyme of 11-HSD have been detected in all kindreds with AME. We expressed enzymes carrying all known missense mutations in cultured cells and determined their activity. For each patient with AME, we compared the enzymatic activity predicted by the genotype with the ratio of cortisol to cortisone metabolites in the urine, (THF + aTHF)/THE. These were strongly correlated, suggesting that the biochemical phenotype of AME is largely determined by genotype. The K isozyme of 11-HSD is also expressed in high levels in the placenta, where its function is unclear. AME patients often have low birth weight. By analogy with AME, low placental 11-HSD K activity in humans might be a risk factor for low birth weight and subsequent hypertension. However, we found that there was no significant correlation between 11-HSD activity, mRNA levels, and either fetal or placental weight.

Original languageEnglish (US)
Pages (from-to)83-88
Number of pages6
JournalSteroids
Volume62
Issue number1
DOIs
StatePublished - Jan 1 1997

Keywords

  • aldosterone
  • cortisol
  • cortisone
  • hypertension
  • kidney
  • mineralocorticoid receptor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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