Adrenocortical
hormone excess, due to primary
aldosteronism (PA) or hypercortisolemia, causes
hypertension and cardiovascular complications. In PA, hypomethylation of
aldosterone synthase (
CYP11B2) is associated with
aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (
CYP11B1), which catalyzes
cortisol biosynthesis and is highly homologous to
CYP11B2, is unclear. The aims of our study were to determine whether the
CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with
cortisol-producing
adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the
CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of
protein kinase A (PRKACA) or the
guanine nucleotide-
binding protein subunit alpha (GNAS) gene, the
CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced
CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the
CYP11B1 promoter plays a role in the regulation of
CYP11B1 expression and
cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the
CYP11B1 promoter.