Adrenal zonation: clues from 11β-hydroxylase and aldosterone synthase

doi:10.1016/S0303-7207(99)00051-9

Molecular and Cellular Endocrinology

Volume 151, Issues 1–2, 25 May 1999, Pages 151-160

https://doi.org/10.1016/S0303-7207(99)00051-9 Get rights and content

Abstract

Aldosterone and cortisol are the major mineralocorticoid and glucocorticoid produced by the human adrenal. Circulating levels of angiotensin II and potassium control the adrenal production of aldosterone, while the production of cortisol is controlled mainly by adrenocorticotropin. The capacity of the adrenal cortex to differentially produce aldosterone and cortisol relies to a large degree on the expression of aldosterone synthase (CYP11B2) and 11β-hydroxylase (CYP11B1). CYP11B2 catalyzes the final steps in the biosynthesis of aldosterone and is expressed solely in the glomerulosa of the adrenal cortex, while CYP11B1 catalyzes the final steps in the biosynthesis of cortisol and is expressed in the fasciculata/reticularis. The zonal expression of these two isozymes appears to result from transcriptional regulation of the two genes. Herein, the recent progress in defining the cellular mechanisms that regulate transcription of these two isozymes and thus the capacity of the adrenal gland to differentially produce aldosterone and cortisol is discussed.

Section snippets

Zone-specific aldosterone and cortisol biosynthesis

The histology of the three concentric zones of the mammalian adrenal cortex namely the zona glomerulosa, zona fasciculata, and zona reticularis was originally described in 1866 (Arnold, 1866). These zones have functionally distinct roles in steroid hormone production; namely, the zona glomerulosa synthesizes mineralocorticoids, the zona fasciculata produces glucocorticoids and, in the human, the zona reticularis produces C₁₉ steroids (so-called adrenal androgens). There are two major unanswered

Corticotropin

It is apparent that there must be unique signaling pathways for the synthesis of aldosterone and cortisol biosynthesis, otherwise both hormones would simply be regulated by corticotropin (ACTH). ACTH is necessary for regulating production of glucocorticoid, by the adrenal fasciculata and also regulates the expression of steroid metabolizing enzymes including 11β-hydroxylase (Miller, 1988, Waterman and Bischof, 1997). Increasing circulating levels of ACTH will increase CYP11B1 expression while

Bovine

Cattle, pigs, sheep, and bullfrogs perform 11β-hydroxylation, 18-hydroxylation, and 18-oxidation though the action of one 11β-hydroxylase, the product of one gene (CYP11B) (Yanagibashi et al., 1986, Nonaka et al., 1995). Immunohistochemical studies in cattle have shown this enzyme is expressed in the fasciculata and to a lesser degree in the glomerulosa of the adrenal cortex (Mitani et al., 1982, Sugano et al., 1985). The mechanisms that control the ability of this single enzyme to convert

Summary

ANG II, K⁺, and ACTH utilize unique mechanisms to differentially regulate the transcription of CYP11B1 and CYP11B2. Adrenal zone-specific expression of these genes is of particular interest because they determine the capacity of the adrenal glomerulosa and fasciculata to produce aldosterone or cortisol. The CYP11B1 and CYP11B2 genes use both different and shared cis-regulatory elements to control their transcription. Defining the exact nature of these elements may provide novel insights into

Acknowledgements

The authors wish to acknowledge the support of the National Institutes of Health (DK4314 to WER). In addition, the authors would like to acknowledge the editorial assistance of Dr Keith Parker.

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Humans have two isozymes with 11β-hydroxylase activity that are respectively required for cortisol and aldosterone synthesis. CYP11B1 (11β-hydroxylase) converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone, is expressed at high levels, and is regulated by ACTH. CYP11B2 (aldosterone synthase) is normally expressed at low levels and is regulated mainly by angiotensin II and potassium levels. The latter enzyme also has 18-hydroxylase and 18-oxidase activities and thus can synthesize aldosterone from deoxycorticosterone. Mutations in the CYP11B1 gene cause steroid 11β-hydroxylase deficiency, a form of congenital adrenal hyperplasia. Mutations in CYP11B2 result in aldosterone synthase deficiency, which can cause hyponatremia, hyperkalemia, and hypovolemia in infancy. These are both recessive disorders. Unequal crossing over between the CYP11B genes can generate a duplicated chimeric gene, causing glucocorticoid-suppressible hyperaldosteronism, an autosomal dominant form of hypertension. Frequent polymorphisms in these genes can affect aldosterone secretion and risk of hypertension.
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Cytochrome P450 11B2 (CYP11B2), also known as aldosterone synthase, is predominantly expressed in the zona glomerulosa of the adrenal gland. As a member of the cytochrome P450 (CYP) superfamily, CYP11B2 plays an important role in three sequential oxidative reactions that catalyzes the synthesis of ALD20,21. Moreover, it has gained greater attention as a promising target for the treatment of hyperaldosteronism-related cardiovascular diseases.
Hyperaldosteronism is a common disease that is closely related to endocrine hypertension and other cardiovascular diseases. Cytochrome P450 11B2 (CYP11B2), an important enzyme in aldosterone (ALD) synthesis, is a promising target for the treatment of hyperaldosteronism. However, selective inhibitors targeting CYP11B2 are still lacking due to the high similarity with CYP11B1. In this study, atractylenolide-I (AT-I) was found to significantly reduce the production of ALD but had no effect on cortisol synthesis, which is catalyzed by CYP11B1. Chemical biology studies revealed that due to the presence of Ala320, AT-I is selectively bound to the catalytic pocket of CYP11B2, and the C8/C9 double bond of AT-I can be epoxidized, which then undergoes nucleophilic addition with the sulfhydryl group of Cys450 in CYP11B2. The covalent binding of AT-I disrupts the interaction between heme and CYP11B2 and inactivates CYP11B2, leading to the suppression of ALD synthesis; AT-I shows a significant therapeutic effect for improving hyperaldosteronism.
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Adrenal zonation: clues from 11β-hydroxylase and aldosterone synthase

Abstract

Section snippets

Zone-specific aldosterone and cortisol biosynthesis

Corticotropin

Bovine

Summary

Acknowledgements

Biochem. Biophys. Res. Commun.

Mol. Cell. Endocrinol.

J. Biol. Chem.

FEBS Lett.

Mol. Cell. Endocrinol.

J. Biol. Chem.

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Biochem. Biophys. Res. Comm.

J. Steroid. Biochem. Molec. Biol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Studies on the mechanisms of ACTH-induced inhibition of aldosterone biosynthesis in the rat adrenal cortex

J. Endocrinol.

Sodium restriction increases aldosterone biosynthesis by increasing late pathway, but not early pathway, messenger ribonucleic acid levels and enzyme activity in normotensive rats

Endocrinology

Mechanisms of inhibition of aldosterone secretion by adrenocorticotropin

Endocrinology

Regulation of adrenal steroidogenesis during chronic stress

Endocr. Res.

Targeted ablation of pituitary pre-opiomelanocortin cells by herpes simplex virus-1 thymidine kinase differentially regulates mRNAs encoding the adrenocorticotropin receptor and aldosterone synthase in the mouse adrenal gland

Mol. Endocrinol.

Ein Beitrag zu der feiner Struktur und dem Chemismus der Nebennieren

Virchows. Arch. Pathol. Anat. Physiol. Klin. Med.

Variations in guanine-binding proteins (Gs, Gi) in cultured bovine adrenal cells: consequences on the effects of phorbol ester and angiotensin II on adrenocorticotropin-induced and cholera-toxin-induced cAMP production

Eur. J. Biochem.

Human NCI-H295 adrenocortical carcinoma cells: a model for angiotensin-II-responsive aldosterone secretion

Endocrinology

Regulation of type 1 angiotensin II receptor messenger ribonucleic acid expression in human adrenocortical carcinoma H295 cells

Endocrinology

Ca(2+)-regulated expression of steroid hydroxylases in H295R human adrenocortical cells

Endocrinology

Differential control of 17 alpha-hydroxylase and 3 beta-hydroxysteroid dehydrogenase expression in human adrenocortical H295R cells

J. Clin. Endocrinol. Metab.

Identification and characterization of two upstream elements that regulate adrenocortical expression of steroid 11 beta-hydroxylase

Mol. Endocrinol.

Hypothesis: aldosterone is synthesized by an alternative pathway during severe sodium depletion: ‘a new wine in an old bottle’

Clin. Exp. Pharmacol. Physiol.

Angiotensin II receptors in the human adrenal gland

Endocr. Res.

Targeting deletion of angiotensin type 1B receptor gene in the mouse

Am. J. Physiol. Renal Fluid Electrolyte Physiol.

Calcium regulates human CYP11B2 transcription

Endocr. Res.

Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements

Mol. Endocrinol.

The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex

Mol. Endocrinol.

Different isozymes of mouse 11 beta-hydroxylase produce mineralocorticoids and glucocorticoids

Mol. Endocrinol.

Zone-specific localization of cytochrome P45011B1 in human adrenal tissue by PCR-derived riboprobes

Histochem. Cell. Biol.

The effect of chronic low-dose infusion of ACTH (1–24) on renin, renin substrate, aldosterone and other corticosteroids in sodium replete and deplete man

Acta Endocrinol.

Cooperative transcription activation between Ad1, a CRE-like element, and other elements in the CYP11B gene promoter

J. Biochem.

Control of aldosterone production by angiotensin II is mediated by two guanine nucleotide regulatory proteins

Endocrinology