Enzyme-mediated protection of the mineralocorticoid receptor against progesterone in the human kidney.
Progesterone (P) is a mineralocorticoid (MC)-antagonist in vitro. During pregnancy, plasma P concentrations exceed aldosterone concentrations at least 50-fold, but plasma aldosterone increases only 4-8-fold in a compensatory manner. Since the in vivo anti-MC activity of P seems to be only moderate, we hypothesized that P is metabolized by enzymes of MC target tissue similar to the way cortisol is metabolized by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2 in order to protect the MC receptor. We, therefore, examined P metabolism using 4-(14)C-P in subcellular fractions of human postmenopausal and male kidneys, and in homogenates of one premenopausal kidney. We found that P is converted effectively, even at high P concentrations (10(-6) mol/l), to various metabolites: 20alpha-dihydro(DH)-P; 17alpha-OH-P; 17alpha-OH,20alpha-DH-P; 5alpha-DH-P; 3beta,5alpha-tetrahydro(TH)-P; and 20alpha-DH,5alpha-DH-P. Homogenates of premenopausal kidney also showed conversion to 3alpha- and 5beta-reduced P metabolites. These results confirm the existence of an efficient renal enzyme system as a possible mechanism of an enzyme-mediated MC receptor selectivity.
Quinkler
M
M
Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universität, Hindenburgdamm 30, 12200, Berlin, Germany. lepeniesquinkler@compuserve.com
Johanssen
S
S
Bumke-Vogt
C
C
Oelkers
W
W
Bähr
V
V
Diederich
S
S
D004092:20-alpha-Dihydroprogesterone / Q000378:metabolism; D002250:Carbon Radioisotopes; D002467:Cell Nucleus / Q000201:enzymology; D003600:Cytosol / Q000201:enzymology; D005260:Female; D006801:Humans; D007668:Kidney / Q000201:enzymology* / Q000648:ultrastructure; D007672:Kidney Cortex / Q000201:enzymology; D007679:Kidney Medulla / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D000451:Mineralocorticoid Receptor Antagonists; D008928:Mitochondria / Q000201:enzymology; D017698:Postmenopause; D017697:Premenopause; D011374:Progesterone / Q000378:metabolism* / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000201:enzymology
D002250:Carbon Radioisotopes; D000451:Mineralocorticoid Receptor Antagonists; D004092:20-alpha-Dihydroprogesterone; D011374:Progesterone