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PubMed1992

Ontogeny and subcellular localization of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) in the human and rat adrenal, ovary and testis.

Primates are unique in having adrenals that secrete large amounts of the precursor sex steroids (PSS) dehydroepiandrosterone (DHEA) and especially DHEA-sulfate. The adrenal PSS require the action of 3 beta-hydroxysteroid dehydrogenase/5-ene-4 ene isomerase (3 beta-HSD), 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), 5 alpha-reductase and/or aromatase to form the androgen dihydrotestosterone (DHT) or the estrogens 17 beta-estradiol and androst-5-ene-diol. Knowing the crucial role of 3 beta-HSD and 17 beta-HSD in sex steroid biosynthesis both in classical as well as in peripheral steroidogenic tissues, we have concentrated our efforts on the elucidation of the molecular structure of these enzyme families. We have thus characterized two types of human 3 beta-HSD cDNA clones and their corresponding genes which encode deduced proteins of 371 and 372 amino acids and share 93.5% homology. Human type I 3 beta-HSD is the almost exclusive mRNA species expressed in the placenta and skin, while human type II is the predominant mRNA species in the adrenals, ovaries and testes. We have also recently elucidated the structure of three types of rat 3 beta-HSD cDNAs which all encode a 372 amino acid protein. The predicted rat type I and II 3 beta-HSD proteins expressed adrenals, gonads and adipose tissue share 94% homology while they share 80% similarity with the liver-specific type III 3 beta-HSD. Transient expression of human type I and II as well as rat type I and II 3 beta-HSD cDNAs in HeLa human cervical carcinoma cells reveals that 3 beta-ol dehydrogenase and 5-ene-4-ene isomerase activities reside within a single protein and that these cDNAs encode functional 3 beta-HSD proteins. The expressed rat type III protein possesses a unique property catalyzing selectively the reduction of 3 beta-androstane 5 alpha-steroids such as DHT. Furthermore, we have also demonstrated by site-directed mutagenesis that the lower activity of expressed rat type II compared to rat type I 3 beta-HSD protein is due to a change of four amino acid residues potentially involved in a membrane-spanning domain. In parallel, we have characterized the complete nucleotide sequence of human 17 beta-HSD cDNA clones encoding a 327 amino acid protein as well as two in tandem 17 beta-HSD genes. Two major 17 beta-HSD mRNA species have been detected in several tissues due to a tissue-specific alternative site of initiation of transcription.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Glands↗
PubMed1993

Evidence that biphasic effects of basic fibroblast growth factor on 5-ene-3 beta-hydroxysteroid dehydrogenase-isomerase activity in cultured immature Leydig cells are mediated by binding to heparan sulfate proteoglycans.

The present studies examined the effects of heparin, heparinase, insulin or insulin-like growth factor-I on basic fibroblast growth factor actions on 5-ene-3 beta-hydroxysteroid dehydrogenase-isomerase activity of cultured immature rat Leydig cells. Treatment with basic fibroblast growth factor alone (0.025-20 ng/ml) for 2 days had a biphasic effect on enzyme activity, with lower concentrations (0.025-1 ng/ml) progressively inhibiting activity to approximately 20% of control, while higher concentrations (2.5-20 ng/ml) partially reversed the inhibitive effects. The inclusion of 10 micrograms/ml heparin, a concentration reported to inhibit growth factor binding to heparan sulfate proteoglycans, blocked the increase in enzyme activity elicited by higher growth factor concentrations, but had no effect on the progressive decline in activity due to lower concentrations. Concomitant treatment with heparinase I and III, which specifically hydrolyze heparan sulfate proteoglycans, had a similar effect. In addition, both insulin and insulin-like growth factor-I partially reversed the inhibition of enzyme activity due to treatment with 1 ng/ml basic fibroblast growth factor. These studies suggest that some basic fibroblast growth factor actions on cultured immature Leydig cells are mediated by binding to heparan sulfate proteoglycans, and that both insulin and insulin-like growth factor-I can reverse the inhibitive effects on 5-ene-3 beta-hydroxysteroid dehydrogenase-isomerase activity.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

Structure-function relationships and molecular genetics of the 3 beta-hydroxysteroid dehydrogenase gene family.

The isoenzymes of the 3 beta-hydroxysteroid dehydrogenase/5-ene-4-ene-isomerase (3 beta-HSD) gene family catalyse the transformation of all 5-ene-3 beta-hydroxysteroids into the corresponding 4-ene-3-keto-steroids and are responsible for the interconversion of 3 beta-hydroxy- and 3-keto-5 alpha-androstane steroids. The two human 3 beta-HSD genes and the three related pseudogenes are located on the chromosome 1p13.1 region, close to the centromeric marker D1Z5. The 3 beta-HSD isoenzymes prefer NAD+ to NADP+ as cofactor with the exception of the rat liver type III and mouse kidney type IV, which both prefer NADPH as cofactor for their specific 3-ketosteroid reductase activity due to the presence of Tyr36 in the rat type III and of Phe36 in mouse type IV enzymes instead of Asp36 found in other 3 beta-HSD isoenzymes. The rat types I and IV, bovine and guinea pig 3 beta-HSD proteins possess an intrinsic 17 beta-HSD activity specific to 5 alpha-androstane 17 beta-ol steroids, thus suggesting that such "secondary" activity is specifically responsible for controlling the bioavailability of the active androgen DHT. To elucidate the molecular basis of classical form of 3 beta-HSD deficiency, the structures of the types I and II 3 beta-HSD genes in 12 male pseudohermaphrodite 3 beta-HSD deficient patients as well as in four female patients were analyzed. The 14 different point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene predominantly expressed in the placenta and peripheral tissues. The mutant type II 3 beta-HSD enzymes carrying mutations detected in patients affected by the salt-losing form exhibit no detectable activity in intact transfected cells, at the exception of L108W and P186L proteins, which have some residual activity (approximately 1%). Mutations found in nonsalt-loser patients have some residual activity ranging from approximately 1 to approximately 10% compared to the wild-type enzyme. Characterization of mutant proteins provides unique information on the structure-function relationships of the 3 beta-HSD superfamily.

3-Hydroxysteroid Dehydrogenases↗
PubMed2006

Enhanced 11beta-hydroxysteroid dehydrogenase activity, the metabolic syndrome, and systemic hypertension.

Metabolic syndrome, with its attendant cardiovascular complications, is reaching epidemic proportions worldwide; hence, there is intense interest in understanding the pathogenesis of and developing therapy for these common disorders. Recent studies have suggested that metabolic syndrome may be a stress response, with an underlying abnormality in the enzyme 11beta-hydroxysteroid dehydrogenase. At the cellular level, the enzyme hydroxysteroid dehydrogenase type 1 (HSD1) locally regenerates active cortisol from inactive cortisone, amplifying glucocorticoid receptor activation and promoting preadipocyte differentiation and adipocyte hypertrophy. Although initial studies in transgenic mice and humans are encouraging, more data are required to conclusively prove the hypothesis that the adipose-tissue-specific overexpression of HSD1 and the resultant increase in tissue-specific cortisol concentrations result in human obesity, insulin resistance, high blood pressure, and metabolic syndrome. Currently, selective inhibitors of HSD1 are not available for human use; however, their development is under way. The use of potent and selective HSD1 inhibitors will finally confirm or refute this hypothesis and may turn out to be an effective strategy for combating these common maladies.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

An enzymatic cycling method for the determination of serum total bile acids with recombinant 3alpha-hydroxysteroid dehydrogenase.

A highly sensitive enzymatic cycling method was developed for the serum total bile acids assay. We constructed a prokaryotic expression system to prepare the recombinant 3alpha-hydroxysteroid dehydrogenase in place of the natural enzyme and for the first time used it in the total bile acids assay. The production rate of thio-NADH correlated with the bile acids concentration and was measured by the change of absorbance at 405/660 nm. The enzymatic cycling method could detect 0.22 micromol/L total bile acids in serum. Within-run and between-run imprecisions were 1.2-3.7% and 2.3-4.8%, respectively. The calibration curve for total bile acids in serum was linear between 0.5 and 180 micromol/L. This method was free from interference by bilirubin, hemoglobin, ascorbate, and lactate dehydrogenase. In conclusion, serum total bile acids could be measured by the enzymatic cycling method with recombinant 3alpha-hydroxysteroid dehydrogenase as the tool enzyme.

3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)↗
PubMed2004

Novel 18beta-glycyrrhetinic acid analogues as potent and selective inhibitors of 11beta-hydroxysteroid dehydrogenases.

Extensive structural modifications to the 18beta-glycyrrhetinic acid template are described and their effects on the SAR of the 11beta-hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. Isoform selective inhibitors have been discovered and compound 7 N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide is highlighted as a very potent selective inhibitor of 11beta-hydroxysteroid dehydrogenase 2 with an IC(50) = 4pM.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

A novel 18 beta-glycyrrhetinic acid analogue as a potent and selective inhibitor of 11 beta-hydroxysteroid dehydrogenase 2.

Using 18beta-glycyrrhetinic acid as a template, the synthesis of a series of secondary amides at the 30-position is described and the effects of these modifications on the SAR of the 11beta-hydroxysteroid dehydrogenase isozymes type 1 and 2 from the rat are investigated. An isoform selective inhibitor has been discovered and compound 5, N-(2-hydroxyethyl)-3beta-hydroxy-11-oxo-18beta-olean-12-en-30-oic acid amide, is highlighted as a very potent and selective inhibitor of 11beta-hydroxysteroid dehydrogenase 2 with an IC(50)=4 pM.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

Cinnamic acid esters as potent inhibitors of fungal 17beta-hydroxysteroid dehydrogenase--a model enzyme of the short-chain dehydrogenase/reductase superfamily.

We present the synthesis of a new family of nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase, designed from flavones and chalcones. Their inhibitory potential was screened on 17beta-hydroxysteroid dehydrogenase from the fungus Cochliobolus lunatus (17beta-HSDcl), a model enzyme of the short-chain dehydrogenase/reductase superfamily. In a series of cinnamates and related coumarin-3-carboxylates, a number of compounds proved to be potent inhibitors of both the oxidative and reductive reactions catalyzed by 17beta-HSDcl, with IC(50) values in the low micromolar range.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

Localization of 17beta-hydroxysteroid dehydrogenase in Mycobacterium sp. VKM Ac-1815D mutant strain.

The localization of mycobacterial 17beta-hydroxysteroid dehydrogenase (17beta-OH SDH) was studied using cell fractionation and cytochemical investigation. Mycobacterium sp. Et1 mutant strain derived from Mycobacterium sp. VKM Ac-1815D and characterized by increased 17beta-OH SDH activity was used as a model organism. Subcellular distribution study showed both soluble and membrane-bound forms of mycobacterial 17beta-hydroxysteroid dehydrogenase. The cytochemical method based on a copper ferrocyanide procedure followed by electron microscopic visualization was applied in order to investigate the intracellular localization of bacterial 17beta-OH SDH in more detail. The enzyme was found to be located in the peripheral cytoplasmic zone adjoining the cytoplasmic membrane (CM). 17beta-OH SDH was loosely membrane bound and easily released into the environment under the cell integrity failure.

17-Hydroxysteroid Dehydrogenases↗
PubMed2005

11beta-Hydroxysteroid dehydrogenase in the heart of normotensive and hypertensive rats.

Corticosteroids have been shown to play a role in cardiac remodeling, with the possibility of a direct effect of overexpression of 11beta-hydroxysteroid dehydrogenase (11HSD) isoform 2 at the level of the cardiomyocytes. The aim of this study was to examine cardiac steroid metabolism in hypertensive rats with hearts that are hypertrophied and fibrotic and have structural alterations in the coronary circulation. To assess possible alterations of cardiac steroid metabolism the expression and activity of both isoforms of 11beta-hydroxysteroid dehydrogenase (11HSD) were studied in spontaneously hypertensive rats (SHR), their normotensive controls Wistar-Kyoto (WKY), and in Dahl salt-sensitive (DS) and salt-resistant rats (DR) kept on a low- or high-salt diet. Using real-time quantitative RT-PCR and enzyme activity assay we found strain-dependent differences in cardiac metabolism of glucocorticoids. In Dahl rats expression of 11HSD1 and 11HSD2 mRNA was lower in DS than in DR rats and was not influenced by dietary salt intake; 11HSD1 mRNA was expressed at higher level than 11HSD2 mRNA. NADP(+)-dependent cardiac 11HSD activity showed similar distribution as 11HSD1 mRNA-lower activity in DS than in DR rats and no effect of salt intake. In SHR and WKY strains 11HSD2 mRNA expression was significantly higher in WKY than in SHR but no differences were observed in 11HSD1 mRNA abundance and NADP(+)-dependent 11HSD activity. These results show that the heart is able to metabolize glucocorticoids and that this metabolism is strain-dependent but do not support the notion of association between cardiac hypertrophy and changes of 11HSD1 and 11HSD2 expression.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

Isolation and characterization of a cDNA encoding mouse 3alpha-hydroxysteroid dehydrogenase: an androgen-inactivating enzyme selectively expressed in female tissues.

3alpha-Hydroxysteroid dehydrogenase catalyzes the transformation of 3-ketosteroids into 3alpha-hydroxysteroids, thus playing an important role in androgen and progesterone metabolism. So far, mouse cDNA and gene encoding 3alpha-HSD has not been reported. In this report, we describe the isolation of a mouse 3alpha-HSD cDNA and the characterization of its substrate specificity and tissue distribution. Sequence analysis indicates that m3alpha-HSD shares 87% amino acid identity with rat 3alpha-HSD. Cells stably transfected with this enzyme catalyze the transformation of dihydrotestosterone (DHT), 5alpha-androstanedione (5alpha-dione) and dihydroprogesterone (DHP) into 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), androsterone (ADT) and 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone), respectively. Quantification of mRNA expression levels of this enzyme was determined in male and female mouse sex-specific tissues using quantitative Realtime PCR. We show that this enzyme is mainly expressed in female-specific tissues while being almost absent from male-specific tissues. In the liver, the same expression level is seen in both male and female, while there is 6-fold higher expression level in female pituitary than in male. These results strongly suggest that m3alpha-HSD could play an important role in the female mouse physiology similar to that of type 1 5alpha-reductase with which it works in tandem. This role could be related to the inactivation of excess of androgen and progesterone that are more severely regulated than in man.

20-alpha-Dihydroprogesterone↗
PubMed2006

Systemic distribution and tissue localizations of human 17beta-hydroxysteroid dehydrogenase type 12.

The 17beta-hydroxysteroid dehydrogenases (HSDs) are enzymes that catalyze the reduction of 17-ketosteroids or the oxidation of 17beta-hydroxysteroids. 17beta-HSD type 12, the most recently cloned member of this gene family, was classified into the 17beta-HSD family based on sequence homology, rather than steroid catalyzing activity. Meanwhile, it has been reported that 17beta-HSD type 12 may be involved in fatty acid synthesis. To better understand the role of 17beta-HSD type 12 in lipid metabolism, we determined the detailed systemic distribution and tissue localizations of 17beta-HSD type 12, which, due partly to the lack of antibodies, had not yet been studied. We carried out these investigations by quantitative reverse transcription (RT)-PCR, Northern blot analysis, and immunohistochemistry, using an antibody against 17beta-HSD type 12 that we have generated. 17beta-HSD type 12 is highly expressed in organs related to lipid metabolism such as liver, kidney, heart and skeletal muscle. 17beta-HSD type 12 is also detected in endocrine-related organs such as pancreas, pituitary gland, adrenal gland, testis and placenta, and in the gastrointestinal tract, which point to the possible involvement of 17beta-HSD type 12 in the regulation of lipid biosynthesis and steroid metabolism. These results support previous reports and solidify the possibility that 17beta-HSD type 12 may play critical roles in the physiological processes, such as fatty acid synthesis, in addition to the steroid metabolism.

17-Hydroxysteroid Dehydrogenases↗
PubMed2006

Characterization of the canine 3beta-hydroxysteroid dehydrogenase and its expression in the corpus luteum during diestrus.

3beta-Hydroxysteroid dehydrogenase (3betaHSD) is a key enzyme in the synthesis of bioactive steroid hormones. Objectives of the present study were to clone canine 3betaHSD and to investigate its expression in dog corpora lutea (CL) covering the periods of their formation, early and late regression (days 5, 15, 25, 35, 45, 65 after ovulation). Complete complementary DNA sequence was amplified by RACE PCR. Subsequent cloning revealed that the canine ovarian 3betaHSD transcript was composed of a 5'-untranslated region (5'-UTR) of 126 nucleotides, an open reading frame (ORF) of 1122 nucleotides and a 3'-UTR of 441 nucleotides. The putative ORF encoded a 374 amino acid protein which remains highly conserved (79-85% identity) between species. The transient expression of the cloned canine 3betaHSD in a mammalian heterologous cell expression system (HEK293T cells) identified the 3betaHSD activity as the only activity of this canine enzyme (absence of any detectable 17-hydroxysteroid dehydrogenase activity). Qualitative RT-PCR revealed expression of 3betaHSD on all days investigated and the signals were strongest on days 5 and 15, with day 25 intensity tending to decrease. However, variability between individual animals was high. The significant decrease in the expression of 3betaHSD towards the end of diestrus as indicated by Real Time PCR (p<0.01) and immunhistochemistry may indicate that the provision of progesterone is controlled by availability of the enzyme rather than the substrate.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Streptozotocin-induced diabetes in the pregnant rat reduces 11 beta-hydroxysteroid dehydrogenase type 2 expression in placenta and fetal kidney.

Several epidemiological and animal studies have shown that the offsprings of diabetic mothers have higher incidences of glucose intolerance, obesity, insulin resistance, and hypertension in later life. It is well known that glucocorticoid metabolism plays a crucial role on several adult disease originated from fetal environment. The aim of this study was to investigate the relation between diabetic pregnancy and glucocorticoid metabolism of both mother and fetus, focusing on the 11 beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. A model of diabetic pregnancy was made by intravenous injection of streptozotocin (35 mg/kg body weight) to Sprague-Dawley rats, and blood and tissue samples were collected on day 20 of pregnancy. In the diabetic group, expression of 11 beta-hydroxysteroid dehydrogenase type 2 in placentas and fetal kidneys was decreased remarkably. Corticosterone levels of diabetic mothers were lower than those of control rats. Despite the differences in maternal corticosterone levels, fetal levels of corticosterone did not differ between the groups. Our results lend support to the concept that diabetic pregnancy imprints glucocorticoid regulation in these fetuses, which may contribute to their increased incidence of higher blood pressure as adults.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2004

Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and proteins.

Four soluble human 3 alpha-hydroxysteroid dehydrogenase (HSD) isoforms exist which are aldo-keto reductase (AKR) superfamily members. They share 86% sequence identity and correspond to: AKR1C1 (20 alpha(3 alpha)-HSD); AKR1C2 (type 3 3 alpha-HSD and bile-acid binding protein); AKR1C3 (type 2 3 alpha-HSD and type 5 17 beta-HSD); and AKR1C4 (type 1 3 alpha-HSD). Each of the homogeneous recombinant enzymes are plastic and display 3-, 17- and 20-ketosteroid reductase and 3 alpha- 17 beta- and 20 alpha-hydroxysteroid oxidase activities with different k(cat)/K(m) ratios in vitro. The crystal structure of the AKR1C2.NADP(+).ursodeoxycholate complex provides an explanation for this functional plasticity. Ursodeoxycholate is bound backwards (D-ring in the A-ring position) and upside down (beta-face of steroid inverted) relative to the position of 3-ketosteroids in the related rat liver 3 alpha-HSD (AKR1C9) structure. Transient transfection indicates that in COS-1 cells, AKR1C enzymes function as ketosteroid reductases due to potent inhibition of their oxidase activity by NADPH. By acting as ketosteroid reductases they may regulate the occupancy of the androgen, estrogen and progesterone receptors. RT-PCR showed that AKRs are discretely localized. AKR1C4 is virtually liver specific, while AKR1C2 and AKR1C3 are dominantly expressed in prostate and mammary gland. AKR1C genes are highly conserved in structure and may be transcriptionally regulated by steroid hormones and stress.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Cooperativity between 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase is based on a common pyridine nucleotide pool in the lumen of the endoplasmic reticulum.

11Beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) is a NADP(H)-dependent oxidoreductase of the ER lumen, which may have an important role in the pathogenesis of metabolic syndrome. Here, the functional coupling of 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase (H6PDH) was investigated in rat liver microsomal vesicles. The results demonstrate the existence of a separate intraluminal pyridine nucleotide pool in the hepatic endoplasmic reticulum and a close cooperation between 11betaHSD1 and H6PDH based on their co-localization and the mutual generation of cofactors for each other.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Active site variability of type 1 11beta-hydroxysteroid dehydrogenase revealed by selective inhibitors and cross-species comparisons.

The NADPH-dependent enzyme type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) activates in a tissue-specific manner circulating pro-glucocorticoid hormones (cortisone in humans) to the 11beta-OH ligand (cortisol in humans), which is able to bind to its cognate receptor and regulate gene transcription. Modulation of this pre-receptor activation mechanism by selective enzyme inhibitors is a desirable goal in the treatment of insulin resistance and related metabolic disorders. Like most other hydroxysteroid dehydrogenases 11beta-HSD1 belongs to the evolutionarily conserved enzyme superfamily of short-chain dehydrogenases/reductases (SDR). The enzyme is anchored within the endoplasmic reticulum through an N-terminal transmembrane domain. In this study we aimed to characterize the active site of mammalian 11beta-HSD1 by determining primary structures from several mammalian lines (cat, hamster, cynomolgus, chimpanzee, dog) thus increasing substantially available sequence information, and allowing us to determine highly variable and constant parts within the primary structure. These regions were mapped to the recently determined three-dimensional structure and are mostly found around the substrate binding site. Furthermore we performed inhibition studies by using different series of inhibitors, comprising 11beta-HSD1 selective arylsulfonamidothiazoles and the unselective steroid-based compound carbenoxolone. The different arylsulfonamidothiazoles display distinct inhibition profiles versus the mammalian species tested, with several tight binding inhibitors for the human enzyme (Ki approximately 50 nM), intermediate for mouse, and weak or not binding inhibitors for rat and guinea pig (Ki>3 microM). Analysis of the inhibition mode reveals that the tight binding inhibitor BVT.528 is a competitive inhibitor for the human form, whereas the related compound BVT.2733 displays a mixed-type inhibition pattern versus the mouse enzyme. Taken together, this structure-activity study provides increased insight into active site complexity and catalytic mechanism of 11beta-HSD1, useful for further inhibitor design.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Physiologic roles of 11beta-hydroxysteroid dehydrogenase type 2 in kidney.

We developed enzyme-linked immunosorbent assays to measure urinary free cortisone (E) and cortisol (F) and analyzed correlations between clinical measures reflecting mineralocorticoid action and 24-hour urinary excretion of E and F or their ratio, uE/F, which has been considered as the most sensitive index of renal 11beta-hydroxysteroid dehydrogenase type 2 activity. Two hundred nineteen healthy men were enrolled in this study. The uE/F ratio was 1.10 +/- 0.41 (mean +/- SD), and a strong linear correlation between uE and uF was observed in a double reciprocal plot. Urinary acid-labile aldosterone excretion had a negative correlation with 24-hour urinary Na excretion and Na/K ratio, but uE/F ratio had a weak positive correlation with the Na/K ratio and no significant correlation with 24-hour urinary Na excretion. In contrast, uE and uF had positive correlations with 24-hour urinary excretions of Na and K, raising the possibility of separate renal effects mediated by the glucocorticoid receptor. Furthermore, uE and uE/F ratio had strong negative correlations with urinary concentrations of Na and K. These results suggest that renal 11beta-hydroxysteroid dehydrogenase type 2 is an important regulatory factor of renal Na and K handlings independently of and/or complementary to the mineralocorticoid action of aldosterone.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗