Aldosterone Secretion: A Molecular Perspective

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Abstract

The major mineralocorticoid hormone aldosterone is secreted from the zona glomerulosa of the adrenal cortex. Aldosterone is synthesized from cholesterol via a series of hydroxylations and oxidations. The enzymes involved in these reactions are mostly members of the cytochrome P450 superfamily. The final steps of this pathway, the conversion of 11-deoxycorticosterone (DOC) to aldosterone, require conversion via the intermediates 18-hydroxy-DOC or corticosterone and 18-hydroxycorticosterone. There are significant differences between species in the number of genes that encode the P45011β-related enzymes (CYP11B) involved in these steps and the zonal distribution of their expression. One enzyme is capable of 11-hydroxylation, 18-hydroxylation, and 18-oxidation of DOC to aldosterone. The genetic basis of four diseases—congenital adrenal hyperplasia due to 11β-hydroxylase deficiency, glucocorticoid-remediable aldosteronism, aldosterone synthase deficiency type I and type II—is explicable by mutations in these cytochrome P45011β-related genes. (Trends Endocrinol Metab 1997;8:346–354). © 1997, Elsevier Science Inc.

Section snippets

• Regulation of Aldosterone Biosynthesis

Since the isolation of aldosterone by Simpson et al. (1954), much has been learned about its biosynthesis, regulation of biosynthesis, modes of actions, and metabolism. The further characterization of aldosterone regulation, particularly of the mechanisms turning off aldosterone secretion, may produce clues to the etiology of hypertensive syndromes that are characterized by over-production of this important mineralocorticoid hormone.

During these past 4 decades, it has become widely accepted

• Aldosterone Biosynthesis

Aldosterone is synthesized from cholesterol, as are the other adrenal steroids. The transport of cholesterol from the outer to the inner mitochondrial membrane is the rate-limiting step in steroidogenesis (Jefcoate et al. 1987). Recently, the carrier protein responsible for this transport has been identified (King et al. 1995). This protein is referred to as the steroidogenic acute regulatory (StAR) protein and is associated exclusively with the mitochondria [refer to review by Stocco and Clark

• Clinical Studies

Characterization of diseases caused by inherited defects in cortisol and aldosterone biosynthesis confirmed the hypothesis that in the human, P45011β is required for normal cortisol synthesis and P450aldo is required for aldosterone synthesis.

Glucocorticoid- (or Dexamethasone-) Remediable Aldosteronism

Glucocorticoid-remediable aldosteronism (GRA), also known as familial hyperaldosteronism type I (FH I), glucocorticoid-suppressible hyperaldosteronism (GSH), or dexamethasone-suppressible hyperaldosteronism (DSH), is a rare disorder that is characterized by moderate hypersecretion of aldosterone, suppressed plasma renin activity (PRA), and rapid correction of these abnormalities after administration of the glucocorticoid dexamethasone. It is a disease showing autosomal dominant inheritance.

In

Acknowledgements

The authors thank Professors J.F. Tait and S.A. Tait for their helpful comments. K.M. Curnow is the recipient of a Fellowship from the Australian Foundation for High Blood Pressure Research. This work has been funded by a block grant to the Howard Florey Institute from NH&MRC of Australia.

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