11 beta-Hydroxysteroid dehydrogenase and its role in the syndrome of apparent mineralocorticoid excess.
Aldosterone, the most important mineralocorticoid, regulates electrolyte excretion and intravascular volume mainly through its effects on renal distal tubules and cortical collecting ducts, where it acts to increase sodium resorption from and potassium excretion into the urine. Excess secretion of aldosterone or other mineralocorticoids, or abnormal sensitivity to mineralocorticoids, may results in hypokalemia, suppressed plasma renin activity, and hypertension. The syndrome of apparent mineralocorticoid excess (AME) is an inherited form of hypertension in which 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is defective. This enzyme converts cortisol to its inactive metabolite, cortisone. Because mineralocorticoid receptors themselves have similar affinities for cortisol and aldosterone, it is hypothesized that the deficiency allows these receptors to be occupied by cortisol, which normally circulates at levels far higher than those of aldosterone. We cloned cDNA and genes encoding two isozymes of 11 beta-HSD. The liver (L) or type 1 isozyme has relatively low affinity for steroids, is expressed at high levels in the liver but poorly in the kidney, and is not defective in AME. The kidney (K) or type 2 isozyme has high steroid affinity and is expressed at high levels in the kidney and placenta. Mutations in the gene for the latter isozyme have been detected in all kindreds with AME. Moreover, the in vitro enzymatic activity conferred by each mutation is strongly correlated with the ratio of cortisol to cortisone metabolites in the urine [tetrahydrocortisone (THF) +allo-THF]/THE. This suggests that the biochemical phenotype of AME is largely determined by genotype.
White
P C
PC
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.
Mune
T
T
Rogerson
F M
FM
Kayes
K M
KM
Agarwal
A K
AK
D042842:11-beta-Hydroxysteroid Dehydrogenases; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D007527:Isoenzymes / Q000235:genetics; D008901:Mineralocorticoids / Q000378:metabolism*; D009154:Mutation; D013577:Syndrome
D018076:DNA, Complementary; D007527:Isoenzymes; D008901:Mineralocorticoids; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases