Impaired renal 11 beta-oxidation of 9 alpha-fluorocortisol: an explanation for its mineralocorticoid potency.
9 alpha-Fluorocortisol (9 alpha FF) is about 200 times more potent as a mineralocorticoid than cortisol (F) in man, although it binds with the same affinity as F and aldosterone to the human mineralocorticoid receptor. The low mineralocorticoid activity of F has been shown to be due to its rapid conversion by the kidney to cortisone (E), which does not bind to the receptor. Therefore, we compared the conversion of F to E with that of 9 alpha FF to 9 alpha-fluorocortisone (9 alpha FE) by 11-hydroxysteroid dehydrogenases in man in vivo and in vitro. Single oral doses of 9 alpha FF, 9 alpha FE, and F were given to normal males, and the excretion of free 9 alpha FF, 9 alpha FE, F, and E was measured in urine. Human kidney and liver slices were incubated with unlabeled steroids, and the free 11-hydroxy- and 11-oxosteroids were quantitated after high performance liquid chromatography separation by UV absorption. Oral F (5 mg) is excreted 70% as free E and 30% as free F (percentage of free steroids only). Oral 9 alpha FF (5 mg) is excreted 90% as free 9 alpha FF and 10% as free 9 alpha FE. Free 9 alpha FF excretion is 14 times greater than that of F after ingesting an identical dose. Oral 9 alpha FE (4 mg) is also excreted 90% as 9 alpha FF and 10% as 9 alpha FE. Kidney slices convert F much faster to E than 9 alpha FF to 9 alpha FE. The conversion of 9 alpha FE to 9 alpha FF is, on the contrary, much faster than that of E to F. Thus, the equilibrium of the reaction is on the 11-oxo side for F/E and on the 11-hydroxy side for 9 alpha FF/9 alpha FE. The interconversion of both pairs of steroids is inhibited by glycyrrhetinic acid in a dose-dependent manner. Liver slices do not measurably convert 9 alpha FF to 9 alpha FE, but do rapidly convert 9 alpha FE into 9 alpha FF. Reflecting this negligible conversion of 9 alpha FF to 9 alpha FE and the low plasma-protein binding of 9 alpha FF, free urinary 9 alpha FF excretion is much higher than that of F after the same oral dose.(ABSTRACT TRUNCATED AT 400 WORDS)
Oelkers
W
W
Department of Endocrinology, Klinikum Steglitz, Freie Universität Berlin, Germany.
Buchen
S
S
Diederich
S
S
Krain
J
J
Muhme
S
S
Schöneshöfer
M
M
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D003348:Cortisone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D005438:Fludrocortisone / Q000378:metabolism* / Q000494:pharmacology / Q000652:urine; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism / Q000494:pharmacology / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000032:analysis / Q000502:physiology*; D007668:Kidney / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008099:Liver / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008901:Mineralocorticoids / Q000032:analysis / Q000378:metabolism*; D010084:Oxidation-Reduction; D018161:Receptors, Mineralocorticoid / Q000032:analysis / Q000378:metabolism
D008901:Mineralocorticoids; D018161:Receptors, Mineralocorticoid; C033001:9-fluorocortisone; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D005438:Fludrocortisone; D003348:Cortisone; D006854:Hydrocortisone