Testosterone inhibits human wild-type and chimeric aldosterone synthase activity in vitro

Abstract

BackgroundFamilial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol did not affect.AimTo explore the direct action of testosterone on ASWT and ASCE enzymes.MethodsHEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities were evaluated incubating HEK-cells transfected with enzymes vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed.ResultsIn this system, testosterone inhibited ASWT (90% inhibition at five µM, IC50=1.690 µM) with higher efficacy and potency than ASCE (80% inhibition at five µM, IC50=3.176 µM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures.ConclusionsThe inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.

The role of sex hormones in aldosterone biosynthesis and their potential impact on its mineralocorticoid receptor

“…Testosterone and the synthetic androgen methylandrostenediol decrease the expression of CYP11B2 mRNA in the adrenal mitochondria of female rats [ 72 ]. Additionally, testosterone and two testosterone analogs inhibit human wild-type aldosterone synthase [ 73 , 74 ].…”