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Original Studies |
Departments of Endocrinology (M.Q., S.J., C.G., V.B., W.O. S.D.) and Urology (M.M.), Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, 12200 Berlin, Germany
Address correspondence and requests for reprints to: Marcus Quinkler, M.D., Division of Endocrinology, Universitätsklinikum Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
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Abstract |
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Although progesterone reaches up to 100 times higher plasma levels in
late pregnancy than aldosterone, the in vivo MC
antagonistic effect of progesterone seems to be relatively weak. One
explanation for this phenomenon could be local metabolism of
progesterone in the human kidney, similar to the inactivation of
cortisol to cortisone by the 11ß-hydroxysteroid dehydrogenase
(11ß-HSD) type 2. We studied the metabolism of progesterone in the
human kidney in vitro and found reduction to
20
-dihydro (DH)-progesterone as the main metabolite. Ring-A
reduction to 5-DH-progesterone, 20-DH-5-DH-progesterone, and
3ß,5-tetrahydro (TH)-progesterone was also documented. We further
showed for the first time that 17-hydroxylation of progesterone
(17-OH-progesterone, 17-OH, 20-DH-progesterone), normally
localized in the adrenals and the gonads, occurs in the human adult
kidney. We found no formation of deoxycorticosterone from progesterone
in the human adult kidney. Using human kidney cortex microsomes, we
tested the inhibitory potency of progesterone and its metabolites on
the 11ß-HSD type 2. The most potent inhibitor was progesterone itself
(IC50 = 4.8 x 10-8 mol/L), followed
by 5-DH-progesterone (IC50 = 2.4 x
10-7 mol/L), 20-DH-progesterone,
3ß,5-TH-progesterone, 17-OH-progesterone, and
20-DH-5-DH-progesterone (IC50 between 7.7 x
10-7 mol/L and 1.3 x 10-6 mol/L). The
least potent inhibitor was 17-OH,20-DH-progesterone. In addition
to progesterone metabolism by the kidney, the inhibition of 11ß-HSD
type 2 by progesterone and its metabolites could be a second
explanation for the weak MC-antagonist activity of progesterone
in vivo. Inhibition of 11ß-HSD type 2 leads to an
increase of intracellular cortisol in a way that the local equilibrium
between the MC agonist cortisol and the antagonist progesterone is
shifted to the agonist side.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsReferences |
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The MC receptor binds aldosterone and cortisol (F) with equal affinity.
Plasma-free F levels are 
50-fold higher than those of aldosterone.
Funder et al. (9) and Edwards et al. (10) found
that the renal 11ß-hydroxysteroid dehydrogenase (11ß-HSD) converts
F into cortisone (E), which does not bind to the MC receptor, whereas
aldosterone is not metabolized by 11ß-HSD. Concerning F, the
selectivity of the MC receptor for aldosterone is, therefore,
enzyme-mediated and not receptor-specific.
In analogy to these findings, we hypothesize that progesterone may be metabolized by enzymes of MC receptor target tissues. We, therefore, studied the progesterone metabolism in human renal cortical and medullary homogenates, as well as in subcellular fractions of human kidneys.
In addition, progesterone and its renal metabolites could influence 11ß-HSD type 2 (11, 12, 13). By inhibiting 11ß-HSD type 2, F could gain more access to the MC receptor, thus offsetting part of the anti-MC effect of progesterone. Therefore, progesterone and its metabolites were tested for their inhibitory potency on 11ß-HSD type 2 in microsomes of human renal cortex.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsReferences |
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4-C14-progesterone (0,02 mCi/mL) and
[1,2,6,7-3H(n)]-F (70.0 Ci/mmol) were obtained
from NEN Life Science Products; unlabelled
progesterone (4-pregnene-3, 20-dione) was from Serva Feinbiochemica
(Heidelberg, Germany). 4-pregnen-17-ol-3, 20-dione
(17-OH-progesterone) and 4-pregnene-21-ol-3, 20-dione
[deoxycorticosterone (DOC)] were purchased from Makor Chemicals Ltd.
(Jerusalem, Israel); and 17-OH,20-DH-progesterone (4-pregnen-17,
20-diol-3-one) was from Paesel and Lorei GmbH and Co. (Frankfurt/M,
Germany).
The following steroids and substances were obtained from Sigma Chemical Co. (St. Louis, MO): F, E, androstenedione
(4-androsten-3, 17-dione), 20-DH-progesterone
(4-pregnen-20-ol-3-one), 20ß-DH-progesterone
(4-pregnen-20ß-ol-3-one), 20-DH-3ß,5-TH-progesterone
(5-pregnane-3ß, 20-diol), 20-DH-3,5ß-TH-progesterone
(5ß-pregnane-3, 20-diol), 20-DH-3,5-TH-progesterone
(5-pregnane-3, 20-diol), 20-DH-5-DH-progesterone
(5-pregnane-20-ol-3-one), 5ß-DH-progesterone (5ß-pregnane-3,
20-dione), 3ß,5-TH-progesterone (5-pregnane-3ß-ol-20-one),
5-DH-progesterone [5-pregnane-3, 20-dione (allo)],
D-glucose-6-phosphate monosodium salt, sucrose,
ß-NAD+ (nicotinamid-adenin-dinucleotid),
ß-NADPH-tetrasodium-salt, and ß-NADH-disodium-salt.
The following steroids were purchased from Steraloids Inc. (Wilton,
NH): 3,5-TH-progesterone (5-pregnane-3-ol-20-one),
3,5ß-TH-progesterone (5ß-pregnane-3-ol-20-one),
20-DH-3ß,5ß-TH-progesterone (5ß-pregnan-3ß, 20-diol),
6ß-OH-progesterone (4-pregnen-6ß-ol-3, 20-dione),
6-OH-progesterone (4-pregnen-6-ol-3, 20-dione),
3ß,5ß-TH-progesterone (5ß-pregnan-3ß-ol-20-one), and
6-OH-3,5ß-TH-progesterone (5ß-pregnan-3,
6-diol-20-one).
Glucose-6-phosphate-dehydrogenase (1000 U/mL) from Leuconostoc mesenteroides was obtained from Boehringer Mannheim (Mannheim, Germany); carbenoxolone and 18ß-glycyrrhetinic acid was from Aldrich-Chemie (Steinheim, Germany); ethylendichloride, n-hexane, 2-propanol, 1-hexanol, methylacetate, 1,2-dichlorethane, 97% sulfuric acid, acetic anhydride, sodiumhydrogen-phosphate-dihydrate, and sodiumhydrogen-phosphate-monohydrat were from Merck Ltd. (Darmstadt, Germany); and methanol in LiChrosolv-quality was from J.T. Baker B.V. (Deventer, the Netherlands).
Human kidney tissue, in the urology department of our hospital, was taken from unaffected kidney segments that were removed because of renal cell carcinoma (14).
Methods
Metabolism experiments Preparation and incubation of homogenates. We used kidneys of two males (56 and 58 yr of age) and two postmenopausal women (52 and 67 yr of age). Cortex and medulla were separated macroscopically. The tissue of each patient was cut immediately into small pieces and homogenized separately (Ultra-Turrax TP18 from Janke and Kunkel GmbH, Staufen, Germany; Potter S from B. Braun) with sodium-phospate buffer (0.01 mol/L, pH 7.0) and 0.25 mol/L sucrose. All steps of preparation were performed on ice. Renal cortex (n = 3 for each patient) and medulla (n = 3 for each patient) were incubated without or with cosubstrate (10-3 mol/L NADH or NADPH) and a NADH/NADPH-regenerating enzyme system (containing 10-2 mol/L glucose-6-phosphate and 10 U glucose-6-phosphate-dehydrogenase). Total incubation volume was 1 mL (pH 7.0) containing 150 mg homogenized tissue, 200.000 cpm 4-C14-progesterone (10-9 mol/l) dissolved in 10 µl methanol, cosubstrate and regenerating system or blanks. Incubation time was 120 min in a 37 C heated shaking water bath. The incubation was stopped by placing the incubating set on ice and adding 1 mL methylacetate to each well.
Preparation and incubation of subcellular fractions: Renal cortex and medulla from eight male patients (age 51–75 yr of age) were cut into small pieces and homogenized as described before. All subsequent steps were performed at 0–4 C using the method of Lakshmi and Monder (15). The homogenates were centrifuged at 750 x g for 30 min. The pellet was disposed, and the supernatant was centrifuged at 20,000 x g for 30 min. The pellet containing the mitochondria was stored in liquid nitrogen. The supernatant was centrifuged at 105,000 x g for 60 min. The generated new supernatant was frozen as cytosolic fraction. The pellet was resuspended in the homogenizing buffer and centrifuged again at 105,000 x g for 60 min. The washed microsomal pellets were resuspended in sodium-phosphate buffer and stored in liquid nitrogen. The subcellular fractions were used within 10 months, and no loss in enzyme activity was seen during this period. Protein was quantified before every incubation using Bradford analysis (Bio-Rad Laboratories, GmbH, München, Germany).
After preliminary studies for time kinetics, protein kinetics, and cosubstrate preferences (data not shown), we determined the following conditions for all subcellular incubations (each with n = 5): the incubation time was 2 h in a shaking water bath (37 C); the total incubation volume was 1 mL (pH 7.0), the cosubstrate concentration (NADPH) was always 10-3 mol/L, the amount of protein in each well was 800 µg, and all incubations included the coenzyme-regenerating system described above. Additional incubations (n = 3) were performed with increasing concentrations (10-8 to 10-6 mol/L) of unlabelled progesterone in the cytosolic and microsomal fraction of kidney cortex. The incubation was stopped by placing the incubation system on ice and by adding 1 mL methylacetate to each well.
Extraction and detection of progesterone and its metabolites. For extraction of the steroids and detection by two-dimensional thin-layer chromatography (TLC), we modified the methods described by Blom et al. (16) and Nienstedt (17, 18).
Each well was centrifuged at 1000 x g and 4 C for 20 min. The upper phase containing methylacetate and the steroids was pipetted into a separate tube. To the remaining lower phase, 700 µL methylacetate were added, vortexed, and centrifuged again. The upper phase was separated, and the lower phase was resuspended. The washing procedure was repeated four times. The radioactivity of the remaining lower phase containing buffer and possible water soluble-conjugated steroids was checked in a ß-counter (Minaxi Tri-Carb 4000 Series; Packard Instruments B.V., Groningen, the Netherlands) and was always less than five percent. The collected upper phases (free steroid fractions) were evaporated and stored at -20 C until detection.
TLC. The free steroid fractions were redissolved in methanol and pipetted onto TLC plates (TLC-alumina plates 20 x 20 cm, coated with silicagel 60F254; Merck Ltd., Darmstadt, Germany). A methanol solution (10 µL) with 20 unlabelled authentic reference steroids (containing 10 µg of each steroid; see materials listed above) was pipetted on the TLC plate starting point, as well. One TLC plate was used for each sample. The plates were run two-dimensionally using a mixture of methylacetate-ethylendichloride (65:35) for one direction (50 min), and hexanol-hexane (75:25) for the other direction (210 min).
After drying the plates at 150 C for 30 min, they were scanned for
radioactivity with a Berthold Linear Analyzer LB284/LB285 Chroma 2D
(with 90% argon and 10% methan gas; Berthold GmbH and Co., Wildbad, Germany), and a recovery of 63% was
calculated. No corrections for estimated average losses were made. The
total sum of radioactivity (progesterone and metabolites) found was
defined as 100%, and the percentage of the newly formed metabolites
are being reported. For identification of the newly formed metabolites,
the added unlabelled reference steroids were stained with
Liebermann-Burchard reagent (ethanol-acetic anhydride-sulfuric acid),
heated at 115 C for 30 min, and located under UV light (360 nm) (Fig. 1
). Due to the RF-values
(ratio of velocity of the solute relative to the velocity of the
solvent front) and the RM-values (log10
(1/RF -1) (17), the radioactive metabolites were
identified.
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-DH-progesterone and
20ß-DH-progesterone by TLC, we used a normal-phase high-performance
liquid chromatography (HPLC) for these steroids. An aliquot of each
free steroid fraction and a mixture of unlabelled reference steroids
(progesterone, androstenedione, 20-DH-progesterone, and
20ß-DH-progesterone) were injected into the HPLC column that was run
with an isocratic solvent mixture (95% hexane and 5% 2-propanol,
flow-rate 1.3 mL/min) for 20 min. The steroids were located on the
chromatogram by UV-detection (240 nm) and by C14-detection
using a radioactivity monitor, as described previously (14). The
progesterone metabolite, located on the 20ß-DH-/20-DH-progesterone
spot in the TLC, showed the retention time of 20-DH-progesterone,
and not as 20ß-DH-progesterone, in the HPLC chromatogram.
11ß-HSD type 2 experiments.Microsomes were prepared from
kidney cortex of six different kidneys (three male and three female
patients; age, 47–81 yr; mean, 60 yr), as described previously (19).
Protein quantification was done by Bradford analysis. The incubation
conditions were constant: the total incubation volume was 1 mL, the
cosubstrate (NAD+) was 1 mmol/L, 100.000 cpm
3H-F (2 nmol/l) as tracer and 25 nmol/l unlabelled F, using
a 0.1 mol/L sodium phosphate buffer (pH 8.0), and progesterone and its
metabolites (5-DH-progesterone, 20-DH-progesterone,
17-OH-progesterone, 17-OH, 20-DH-progesterone,
20-DH-5-DH-progesterone, and 3ß, 5-TH-progesterone) in
concentrations ranging from 10-9 to 10-5
mol/L as inhibitors. Carbenoxolone and glycyrrhetinic acid were used as
reference inhibitor substances. The incubation time was 30 min. The
incubation was started by the addition of microsomes (0.03 mg/mL) to
10-min preincubated wells containing all assay components, except the
enzyme preparation. In all assays, blanks were included containing all
assay components, except buffer, instead of the enzyme preparation.
Incubations were terminated by the addition of 2 mL cold methanol and
by transfer on ice. The steroids were extracted by Sep-Pak
C18-cartridges (Waters Millipore Corp. GmbH,
Eschborn, Germany). The separation of F and E was performed by TLC, as
described previously (19). The steroid spots were identified under UV
light, cut out, and transferred to scintillation vials. The cut out
pieces containing F or E were incubated in a scintillation liquid for
12 h. The amounts of F and E were measured in a ß-counter so
that the percentage conversion could be calculated.
Statistics: Student’s t test was used for
statistical calculations comparing the amount of each progesterone
metabolite formed in cortical vs.
medullary cytosol and
in cortical vs. medullary microsomes (Table 1). Duncan’s multiple range test was
used for multiple comparisons of progesterone metabolites formed in the
presence of increasing amounts of unlabelled progesterone (Fig. 3).
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Metabolism experiments
Homogenates.In renal homogenates, no conjugated progesterone
metabolites were found, and the progesterone metabolism was low without
the NADH/NADPH-regenerating system (data not shown). NADPH was the
preferred cosubstrate for progesterone metabolism in renal homogenates.
The main renal progesterone metabolite found in both sexes was
20-DH-progesterone (Fig. 2). We also
found 17-OH-progesterone and 17-OH,20-DH-progesterone.
Ring-A reduction was also detectable, leading to the formation of
5-DH-progesterone, 20-DH-5-DH-progesterone, and
3ß,5-TH-progesterone. We found no formation of DOC from
progesterone in adult kidney homogenates. Metabolism in renal cortex
was of greater diversity and extent than in renal medulla. Female and
male kidney homogenates formed the same progesterone metabolites, but
the intensity of metabolism seems to be greater in female kidney
homogenates.
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-DH-progesterone was the
only metabolite formed (Table 1
). There was no significant difference
in progesterone metabolism between cytosol from renal cortex and
medulla. The cortical and medullary microsomes showed a greater
variability of progesterone metabolites (17-OH-progesterone,
17-OH, 20-DH-progesterone, and 5-DH-progesterone) than
cytosol, but only traces of 3ß,5-TH-progesterone and
20-DH-progesterone were found. In microsomes of the cortex, over
50% of progesterone was metabolized, whereas the medullary microsomes
were less active.
On adding increasing unlabelled progesterone concentrations to kidney
cortex cytosol, the conversion of 14C-progesterone to
20-DH-progesterone decreased slightly, but significantly
(P < 0.01) (Fig. 3).
In cortex microsomes, the conversion to its metabolites, especially to
17-hydroxylated metabolites, was reduced to a greater extent
(P < 0.001) at the highest concentration of added
unlabelled progesterone tested (10-6 mol/L).
11ß-HSD type 2 experiments
Carbenoxolone and glycyrrhetinic acid are known to be potent
inhibitors of 11ß-HSD type 2. Similar to published results, we found
IC50's in the nanomolar range (Table 2). Progesterone and all its renal
metabolites also inhibited the conversion of F to E by 11ß-HSD type 2
in human renal cortex microsomes at F concentrations of 25 nmol/L. Of
these steroids, the most potent inhibitors were progesterone itself
(IC50 = 48 nmol/L) and 5-DH-progesterone
(IC50 = 240 nmol/L) (Table 2), followed by
20-DH-progesterone, 3ß,5-TH-progesterone,
17-OH-progesterone, 20-DH-5-DH-progesterone with similar
IC50 between 0.77 and 1.3 µmol/L. The least
potent inhibitor was 17-OH,20-DH-progesterone, for which no
IC50 could be calculated in the range of
concentrations tested.
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During the luteal phase of the menstrual cycle, progesterone
plasma concentrations range between 30–110 nmol/L. During pregnancy
the concentrations rise steadily until they peak at the end of the 3rd
trimester in the range of 320–700 nmol/L (6, 7). In contrast, plasma
aldosterone increases only slightly during the luteal phase and late
pregnancy (0.6 nmol/L and 5.8 nmol/L, respectively) (8). Regarding the
high-binding affinity of progesterone to the MC receptor (1, 2), it is
still a question how aldosterone can keep its function as effective MC
agonist in the presence of high concentrations of progesterone. Several
explanations have been put forward. First, one should take into account
that only 3% of progesterone is unbound, whereas 80% is weakly
bound to albumin and 17% to corticosteroid-binding globulin. On
the other hand 37% of aldosterone is unbound and thereby available for
intracellular action (20). Second, the half-life of the aldosterone-MC
receptor complex was estimated to be about 600 min compared with 45 min
of the progesterone-MC receptor complex (21). A third mechanism that
possibly keeps the MC receptor clear of the antagonist progesterone is
the extra-adrenal formation of DOC, a weak MC, from plasma
progesterone. Some authors (22, 23, 24, 25) reported DOC biosynthesis in human
fetal kidney tissue, which implies the idea of para- or autocrine
formation of a MC receptor agonist in its site of action. Winkel
et al. (22) found in kidney microsomes of a pregnant woman,
a 65-yr-old woman, and two 56- and 31-yr-old men less than 1%
conversion of progesterone to DOC, but they failed to show any activity
in 10 other kidneys. In our experiments, we found no formation of DOC
from progesterone in adult kidneys. Because the conversion rates of
progesterone to DOC reported by Winkel et al. (22) were
markedly less than 1%, it is possible that our detection system was
too insensitive to measure such low conversion rates. It is also likely
that the conversion of plasma progesterone to DOC varies widely among
individuals, suggesting genetic differences in the capacity of
extra-adrenal 21-hydroxylation. On the other hand, it is possible that
particular hormonal circumstances, like pregnancy or fetal life, are
linked with the capacity of renal conversion of progesterone to
DOC.
Progesterone metabolism
We suggest that the MC receptor is partly protected from high
progesterone concentrations during pregnancy by its metabolic
inactivation similar to the inactivation of F to E by 11ß-HSD type 2.
There are only a few studies on progesterone metabolism in extrahepatic
and extragonadal human tissues. Nienstedt et al. (26)
described progesterone metabolism in the human adult small intestine
with 3ß,5-TH-progesterone, 3,5-TH-progesterone,
20-DH-5-DH-progesterone, and 20-DH-progesterone as the main
metabolites. In the human fetal intestine, metabolism was shifted
toward the 5ß-metabolites. Blom et al. (16) examined
progesterone metabolism in human parotid and submandibular glands, and
Ojanotko-Harri (27) in the human gingiva. Both groups found
20-DH-progesterone and 5-DH-progesterone as the main metabolites.
Until now, progesterone metabolism was described only in the human
fetal kidney with formation of 20-DH-progesterone,
3,5ß-TH-progesterone, 20-DH-3,5ß-TH-progesterone, and DOC
(28).
Our experiments show that progesterone is converted in considerable
quantity into various metabolites in human adult renal tissue with
20-DH-progesterone as the main metabolite. These results are similar
to the metabolite profile described in human parotid and submandibular
glands (16). The preferred cosubstrate with kidney cortex microsomes
was NADPH, and the rate of progesterone inactivation/metabolism
amounted to 50% in 2 h. The 20-HSD seems to be localized
mainly in the cytosol. Recently, Soucy et al. (29) described
the isolation of human 20-HSD cDNA , but until now no studies are
available about human 20-HSD mRNA expression in human tissues. The
other metabolites found suggest the presence of 5-reductase,
3ß-hydroxy-steroid dehydrogenase and, surprisingly,
17-hydroxylase. To our knowledge, this is the first description of the
formation of 17-OH-progesterone from progesterone in the human
adult kidney, which is believed to occur in the adrenals and gonads
only.
Whether the progesterone metabolites found bind to the human MC
receptor and have an antagonist or agonist effect remains to be tested.
So far, only two groups examined the competition between
3H-aldosterone and 17-OH-progesterone and
17-OH,20-DH-progesterone for the ovine and rat MC receptor (30, 31) and found no significant binding of these metabolites.
Incubations with increasing concentrations of unlabelled progesterone
(up to 10-6 mol/L) in human renal cortex cytosol
(Fig. 3a) showed only a small (27.1% to 24.3%), but significant
(P < 0.01), decrease in percentage conversion due to
saturation in metabolic activity, suggesting a very effective and
potent enzyme system (20-HSD). The percentage of 17-hydroxylation in
human renal cortex microsomes (Fig. 3b) is reduced to a greater extend
in the presence of 10-6 mol/L progesterone
(17-OH-progesterone: 31.4% to 23.2%; 17-OH,
20-DH-progesterone: 11.7% to 8.6%). However, more than 40% of
progesterone are metabolized altogether at this high concentration.
Because there was only a small increase in the percentage conversion of
progesterone into metabolites with incubation times longer than 60 min
(data not shown), the metabolism of progesterone in the kidney seems to
occur relatively fast.
Inhibition of 11ß-HSD type 2
Progesterone is a known potent inhibitor of 11ß-HSD type 2, with
IC50 ranging from 6 nmol/L (11) up to 1.1
µmol/L, depending on protein origin and assay (12, 13). There are
only few studies in the literature on inhibition of 11ß-HSD type 2 by
progesterone metabolites (11, 12). We found that the renal 11ß-HSD
type 2 of kidney cortex microsomes is inhibited by progesterone itself
and by the renal progesterone metabolites detected (Table 2). We
demonstrated an inhibition of human renal 11ß-HSD type 2 by
3ß,5-TH-progesterone and 20-DH-5-DH-progesterone for the
first time. Progesterone probably plays the main part in inhibiting
11ß-HSD type 2 due to its low IC50-value and
its high plasma concentration. At least during the 3rd trimester of
pregnancy, it is likely that free and albumin-bound progesterone
concentrations are exceeding 50 nmol/L, the concentration of half
maximal inhibition of 11ß-HSD type 2. Whether 5-DH-progesterone,
the second potent inhibitor, and the other metabolites have a
significant inhibitory influence in vivo is speculative
because no information on intracellular and only few information on
plasma concentrations (20-DH-progesterone: up to 90 nmol/L in 3rd
trimester, 17-OH-progesterone: up to 29 nmol/L in 3rd trimester (32)
are available yet.
The inhibition of 11ß-HSD type 2 by progesterone and its metabolites
could lead to a decreased inactivation of F to E by 11ß-HSD type 2,
and, therefore, to an increase of intracellular F concentration. This
could result in a greater access of F to the MC receptor and,
consequently, in a further decrease of the anti-MC effect of
progesterone on the MC receptor (Fig. 4).
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Inhibition of 11ß-HSD type 2 by progesterone and its metabolites, as described in this article, and a subsequently increased intracellular F (MC agonist) concentration, could be one explanation for MC receptor down-regulation (34) and the decreased PRA and serum aldosterone (33, 35, 36) in preeclampsia. An altered progesterone metabolism in the kidney and an inhibited 11ß-HSD type 2 could, therefore, participate in the pathogenesis of preeclampsia. Walker et al. (42) measured the free F/E ratio in urine of preeclamptic women and found no difference to normal pregnancy, but only a very small number of patients was examined in this report. Very recently, Heilmann et al. (43) confirmed the hypothesis of inhibited 11ß-HSD type 2 in preeclampsia by showing an increased free F/E ratio in the urine of 41 patients with preeclampsia compared with 48 women with normal pregnancy.
In conclusion, we found a marked metabolic activity toward progesterone in human adult kidneys, which could be one mechanism of reducing the MC antagonistic influence of progesterone similar to inactivation of F by 11ß-HSD type 2. Moreover, progesterone and its metabolites are potent inhibitors of 11ß-HSD type 2 and could hereby increase the intracellular F concentration, producing more MC agonist activity.
We are planning to localize the progesterone metabolizing enzymes in the kidney. In this regard, it will be of special interest to find out whether some of these enzymes are colocalized with the MC receptor and the 11ß-HSD type 2 in the distal tubule and the collecting duct.
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Footnotes |
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Received April 27, 1999.
Revised July 22, 1999.
Accepted August 8, 1999.
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M. Quinkler, B. Meyer, W. Oelkers, and S. Diederich Renal Inactivation, Mineralocorticoid Generation, and 11{beta}-Hydroxysteroid Dehydrogenase Inhibition Ameliorate the Antimineralocorticoid Effect of Progesterone in Vivo J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3767 - 3772. [Abstract] [Full Text] [PDF]
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M. Quinkler and P. M. Stewart Hypertension and the Cortisol-Cortisone Shuttle J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2384 - 2392. [Abstract] [Full Text] [PDF]
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M. Quinkler, C. Bumke-Vogt, B. Meyer, V. Bahr, W. Oelkers, and S. Diederich The Human Kidney Is a Progesterone-Metabolizing and Androgen-Producing Organ J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2803 - 2809. [Abstract] [Full Text] [PDF]
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 L. M. Thurston, K. C. Jonas, D. R. E. Abayasekara, and A. E. Michael Ovarian Modulators of 11{beta}-Hydroxysteroid Dehydrogenase (11{beta}HSD) Activity in Follicular Fluid from Bovine and Porcine Large Antral Follicles and Spontaneous Ovarian Cysts Biol Reprod, June 1, 2003; 68(6): 2157 - 2163. [Abstract] [Full Text] [PDF]
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S. Diederich, E. Eigendorff, P. Burkhardt, M. Quinkler, C. Bumke-Vogt, M. Rochel, D. Seidelmann, P. Esperling, W. Oelkers, and V. Bahr 11{beta}-Hydroxysteroid Dehydrogenase Types 1 and 2: An Important Pharmacokinetic Determinant for the Activity of Synthetic Mineralo- and Glucocorticoids J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5695 - 5701. [Abstract] [Full Text] [PDF]
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C. O. Stocco, J. Chedrese, and R. P. Deis Luteal Expression of Cytochrome P450 Side-Chain Cleavage, Steroidogenic Acute Regulatory Protein, 3{beta}-Hydroxysteroid Dehydrogenase, and 20{alpha}-Hydroxysteroid Dehydrogenase Genes in Late Pregnant Rats: Effect of Luteinizing Hormone and RU486 Biol Reprod, October 1, 2001; 65(4): 1114 - 1119. [Abstract] [Full Text] [PDF]
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 N. Farman and M.-E. Rafestin-Oblin Multiple aspects of mineralocorticoid selectivity Am J Physiol Renal Physiol, February 1, 2001; 280(2): F181 - F192. [Abstract] [Full Text] [PDF]
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 A. Odermatt, P. Arnold, and F. J. Frey The Intracellular Localization of the Mineralocorticoid Receptor Is Regulated by 11beta -Hydroxysteroid Dehydrogenase Type 2 J. Biol. Chem., July 20, 2001; 276(30): 28484 - 28492. [Abstract] [Full Text] [PDF]
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