Evidence that corticosterone is not an obligatory intermediate in aldosterone biosynthesis in the rat adrenal.
CGS 16949A is a potent inhibitor of aromatase in vitro with an IC50 of 0.03 microM for the inhibition of LH-stimulated estrogen biosynthesis in hamster ovaries. In vivo, CGS 16949A leads to sequelae of estrogen deprivation (e.g. regression of DMBA-induced mammary tumors) without causing adrenal hypertrophy in adult rats. To complement these in vitro and in vivo findings, the effect of CGS 16949A on adrenal steroid biosynthesis in rats was investigated in vitro and in vivo. The surprising finding in vitro was that CGS 16949A inhibited aldosterone biosynthesis (IC50 = 1 microM) at concentrations 100 times lower than those for inhibition of corticosterone biosynthesis (IC50 = 100 microM). Moreover, deoxycorticosterone (DOC) concentrations were elevated at all concentrations of CGS 16949A which inhibited aldosterone synthesis. The classical biosynthetic pathway for aldosterone is DOC----corticosterone----18-OH-corticosterone----aldosterone. Thus inhibition of aldosterone biosynthesis, reflected in DOC accumulation, without affecting corticosterone concentrations, indicates that corticosterone is not an obligatory intermediate in the conversion of DOC to aldosterone in the rat. In vivo, CGS 16949A showed a suppression of plasma aldosterone in ACTH-stimulated male rats at doses which did not significantly affect plasma corticosterone. In conclusion, aldosterone measured both in vitro and in vivo must be derived primarily from a biosynthetic pathway in which corticosterone is not obligatory intermediate.
Häusler
A
A
Research Department, Ciba-Geigy Ltd, Basel, Switzerland.
Monnet
G
G
Borer
C
C
Bhatnagar
A S
AS
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D047072:Aromatase Inhibitors; D003345:Corticosterone / Q000378:metabolism*; D003366:Cosyntropin / Q000494:pharmacology; D003692:Delayed-Action Preparations; D003900:Desoxycorticosterone / Q000378:metabolism; D017316:Fadrozole; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D047072:Aromatase Inhibitors; D003692:Delayed-Action Preparations; D007093:Imidazoles; D009570:Nitriles; D000616:Aminoglutethimide; D003366:Cosyntropin; D003900:Desoxycorticosterone; D000450:Aldosterone; C006418:adrenocorticotropin zinc; D017316:Fadrozole; D003345:Corticosterone