Disorders of Steroid 11β-Hydroxylase Isozymes*

Abstract

The most active corticosteroids are 11 beta-hydroxylated. Humans have two isozymes with 11 beta-hydroxylase activity that are respectively required for cortisol and aldosterone synthesis. CYP11B1 (11 beta-hydroxylase) is expressed at high levels and is regulated by ACTH, whereas CYP11B2 (aldosterone synthase) is normally expressed at low levels and is regulated by angiotensin II. In addition to 11 beta-hydroxylase activity, the latter enzyme has 18-hydroxylase and 18-oxidase activities and thus can synthesize aldosterone from deoxycorticosterone. Insights into the normal functioning of these enzymes are gained from studies of disorders involving them. Mutations in the CYP11B1 gene cause steroid 11 beta-hydroxylase deficiency, a form of congenital adrenal hyperplasia characterized by signs of androgen excess and by hypertension. Mutations in CYP11B2 result in aldosterone synthase (corticosterone methyloxidase) deficiency, an isolated defect in aldosterone biosynthesis that can cause hyponatremia, hyperkalemia, and hypovolemic shock in infancy and failure to thrive in childhood. These are both recessive disorders. Unequal crossing over between the CYP11B genes can generate a duplicated chimeric gene with the transcriptional regulatory region of CYP11B1 but sufficient coding sequences from CYP11B2 so that the encoded enzyme has aldosterone synthase (i.e. 18-oxidase) activity. This results in aldosterone biosynthesis being regulated by ACTH, a condition termed glucocorticoid-suppressible hyperaldosteronism. This form of genetic hypertension is inherited in an autosomal dominant manner.

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

“…If the elevated plasma levels of corticosterone were of zona fasciculata origin, cortisol and corticosterone would be expected to be increased to a similar extent. Elevated plasma levels of 18-OH-11-deoxycorticosterone should be explained accordingly, since 11b-hydroxylase can convert 11-deoxycorticosterone to 18-OH-11-deoxycorticosterone (22).…”

Quantitative assessment of CYP11B1 and CYP11B2 expression in aldosterone-producing adenomas

“…CYP11B1 catalyzes the 11b-hydroxylation of 11-deoxycortisol to cortisol and of 11-deoxycorticosterone (DOC) to corticosterone and is regulated by adrenocorticotropin (ACTH) (1,2). CYP11B2 catalyzes the 11b-hydroxylation of DOC to corticosterone, the 18-hydroxylation of corticosterone to 18-hydroxycorticosterone , and the 18-oxidation of 18-OHB to aldosterone, predominantly under the control of angiotensin II and K + (1 -3).…”

True

“…34 Mean basal cortisol (r À0.311; P 0.002) and androstenedione (r À0.297; P 0.004) during the OGTT as well as DXM suppressed 17-OHP (r À0.328; P 0.001) were all negatively correlated with WHR suggesting that visceral obesity is associated with decreased production of cortisol and androstenedione. Positive correlations between WHR and cortisol (r 0.221; P 0.031) and 17-OHP (r 0.388; P`0.001) net increments, and between BMI and cortisol (r 0.272; P 0.008) and 17-OHP (r 0.389; P`0.001) net increments suggest increased adrenal sensitivity to ACTH stimulation.…”