The most potent
corticosteroids are 11beta-hydroxylated compounds. In humans, two
cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalysing the biosynthesis of
cortisol and
aldosterone, are present in the adrenal cortex.
CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed on high levels in the zona fasciculata and is regulated by
ACTH.
CYP11B2, the gene encoding
aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system.
Aldosterone synthase has 11beta-hydroxylase activity as well as 18-hydroxylase activity and 18-oxidase activity. The substrate for
CYP11B2 is 11-deoxycorticosterone, that of
CYP11B1 is
11-deoxycortisol. Mutations in
CYP11B1 cause
congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by
androgen excess and
hypertension. Mutations in
CYP11B2 cause congenital
hypoaldosteronism (
aldosterone synthase deficiency) which is characterized by life-threatening
salt loss,
failure to thrive, hyponatraemia and hyperkalaemia in early infancy. Both disorders have an autosomal recessive inheritance. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of
11-deoxycortisol after
ACTH stimulation). In infants with congenital
hypoaldosteronism, a comparable frequency of
18-hydroxylase deficiency (
aldosterone synthase deficiency type I) and of
18-oxidase deficiency (
aldosterone synthase deficiency type II) can be found. Molecular genetic studies of the
CYP11B1 and
CYP11B2 genes in 11beta-hydroxylase deficiency or
aldosterone synthase deficiency have led to the identification of several mutations. Transfection experiments showed loss of
enzyme activity in vitro. In some of the patients with
18-oxidase deficiency (
aldosterone synthase deficiency type II) no mutations in the
CYP11B2 gene were identified. Refined methods for
steroid determination are the basis for the diagnosis of inborn errors of steroidogenesis. Molecular genetic studies are complementary; on the one hand, they have practical importance for the prenatal diagnosis of virilizing CAH forms and on the other hand, they are of theoretical importance in terms of our understanding of the functioning of
cytochrome P450 enzymes. Copyrightz1999S.KargerAG, Basel