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PubMed1998

Specific effect of arachidonic acid on 17beta-hydroxysteroid dehydrogenase in rat Leydig cells.

It is well known that arachidonic acid (AA) acts as an intratesticular factor regulating luteinizing hormone-mediated testicular steroidogenesis. The present studies were conducted to determine the effect of AA on steroidogenic enzymes in rat Leydig cells. Exogenously added AA significantly inhibited 22(R)-hydroxy-cholesterol-stimulated testosterone production, which is a clear indication that AA is acting at some point after cholesterol transport to the inner mitochondrial membrane. AA failed to block the conversion of 22(R)-hydroxycholesterol to pregnenolone, indicating that the cytochrome P-450 side-chain cleavage enzyme complex is not the site of inhibition. The present results demonstrate that only 17beta-hydroxysteroid dehydrogenase seems to be involved in the AA action, since nearly 60% inhibition of testosterone production was found when the cells were incubated with androstenedione. Furthermore, no effect of AA was found when androstenediol was used as substrate in the testosterone synthesis, which indicates that 3beta-hydroxysteroid dehydrogenase is not affected by AA. The conversion of AA to its metabolites is not required for its action on 17beta-hydroxysteroid dehydrogenase and the activation of protein kinase C is not involved in the inhibitory effect.

17-Hydroxysteroid Dehydrogenases↗
PubMed1981

Study of human placental estradiol-17 beta dehydrogenase/20 alpha-hydroxysteroid dehydrogenase by preparative disc-gel electrophoresis.

The soluble enzyme, estradiol-17 beta dehydrogenase from human term placenta, appears to co-purify with a second soluble enzyme, 20 alpha-hydroxysteroid dehydrogenase. The enzyme, which had been partially purified by affinity chromatography, fractionated on a preparative electrophoresis gel to a homogeneous preparation containing both estradiol-17 beta dehydrogenase and 20 alpha-hydroxysteroid dehydrogenase activities in a ratio of approximately 100:1. Analytical polyacrylamide disc-gels resolved this homogeneous preparation as a single band by both protein and activity staining techniques. Homogeneous enzyme inactivated and affinity-radioalkylated by 16 alpha-[2'-14C]bromoacetoxyprogesterone or 16 alpha-[2'-14C] bromoacetoxyestradiol 3-methyl ether, and when analyzed by SDS disc-gel electrophoresis, gave a single protein band which corresponded identically to the radioactivity peaks. These observations support the hypothesis that estradiol-17 beta dehydrogenase and 20 alpha-hydroxysteroid dehydrogenase represent dual oxidoreductase activity in one enzyme. Preparative disc-gel electrophoresis, a technique which has not been previously adapted to purification of these human placental enzyme activities, was useful to rapidly (3 days) effect a 15-fold enrichment of the estradiol-17 beta dehydrogenase specific activity from "heat-treated cytosol". Thus, laboratory-scale preparative disc-gel electrophoresis is useful for rapid, small-scale enrichment of this soluble enzyme.

17-Hydroxysteroid Dehydrogenases↗
PubMed2001

Subcellular targeting analysis of SDR-type hydroxysteroid dehydrogenases.

Most mammalian hydroxysteroid dehydrogenases known thus far belong to the protein superfamilies of short-chain dehydrogenases/reductases (SDR) and aldo-keto reductases (AKR). Whereas members of the AKR family are soluble, cytoplasmic enzymes, SDR-type hydroxysteroid dehydrogenases are also located to other subcellular compartments, i.e. endoplasmic reticulum, mitochondria or peroxisomes. Differential localization might play an important role in influencing the reaction direction of hydroxy dehydrogenase/oxo reductase pathways by determining the available nucleotide cofactor pool. Targeting signals for different subcellular organelles in human hydroxysteroid dehydrogenases have been identified, however, in several enzymes localization signals remain to be determined.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones.

The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily. The enzymes correspond to type 1 3alpha-HSD (AKR1C4), type 2 3alpha(17beta)-HSD (AKR1C3), type 3 3alpha-HSD (AKR1C2) and 20alpha(3alpha)-HSD (AKR1C1), and share at least 84% amino acid sequence identity. All enzymes acted as NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductases and as 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidases. The functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins. Salient features were that AKR1C4 was the most catalytically efficient, with k(cat)/K(m) values for substrates that exceeded those obtained with other isoforms by 10-30-fold. In the reduction direction, all isoforms inactivated 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one; 5alpha-DHT) to yield 5alpha-androstane-3alpha,17beta-diol (3alpha-androstanediol). However, only AKR1C3 reduced Delta(4)-androstene-3,17-dione to produce significant amounts of testosterone. All isoforms reduced oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxy-pregn-4-ene-3,20-dione (20alpha-hydroxyprogesterone). In the oxidation direction, only AKR1C2 converted 3alpha-androstanediol to the active hormone 5alpha-DHT. AKR1C3 and AKR1C4 oxidized testosterone to Delta(4)-androstene-3,17-dione. All isoforms oxidized 17beta-oestradiol to oestrone, and 20alpha-hydroxyprogesterone to progesterone. Discrete tissue distribution of these AKR1C enzymes was observed using isoform-specific reverse transcriptase-PCR. AKR1C4 was virtually liver-specific and its high k(cat)/K(m) allows this enzyme to form 5alpha/5beta-tetrahydrosteroids robustly. AKR1C3 was most prominent in the prostate and mammary glands. The ability of AKR1C3 to interconvert testosterone with Delta(4)-androstene-3,17-dione, but to inactivate 5alpha-DHT, is consistent with this enzyme eliminating active androgens from the prostate. In the mammary gland, AKR1C3 will convert Delta(4)-androstene-3,17-dione to testosterone (a substrate aromatizable to 17beta-oestradiol), oestrone to 17beta-oestradiol, and progesterone to 20alpha-hydroxyprogesterone, and this concerted reductive activity may yield a pro-oesterogenic state. AKR1C3 is also the dominant form in the uterus and is responsible for the synthesis of 3alpha-androstanediol which has been implicated as a parturition hormone. The major isoforms in the brain, capable of synthesizing anxiolytic steroids, are AKR1C1 and AKR1C2. These studies are in stark contrast with those in rat where only a single AKR with positional- and stereo-specificity for 3alpha-hydroxysteroids exists.

3-Hydroxysteroid Dehydrogenases↗
PubMed1984

Purification and properties of a 3 alpha-hydroxysteroid dehydrogenase of rat liver cytosol and its inhibition by anti-inflammatory drugs.

An NAD(P)-dependent 3 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.50) was purified to homogeneity from rat liver cytosol, where it is responsible for most if not all of the capacity for the oxidation of androsterone, 1-acenaphthenol and benzenedihydrodiol (trans-1,2-dihydroxycyclohexa-3,5-diene). The dehydrogenase has many properties (substrate specificity, pI, Mr, amino acid composition) in common with the dihydrodiol dehydrogenase (EC 1.3.1.20) purified from the same source [Vogel, Bentley, Platt & Oesch (1980) J. Biol. Chem. 255, 9621-9625]. Since 3 alpha-hydroxysteroids are by far the most efficient substrates, the enzyme is more appropriately designated a 3 alpha-hydroxysteroid dehydrogenase. It also promotes the NAD(P)H-dependent reductions of quinones (e.g. 9,10-phenanthrenequinone, 1,4-benzoquinone), aromatic aldehydes (4-nitrobenzaldehyde) and aromatic ketones (4-nitroacetophenone). The dehydrogenase is not inhibited by dicoumarol, disulfiram, hexobarbital or pyrazole. The mechanism of the powerful inhibition of this enzyme by both non-steroidal and steroidal anti-inflammatory drugs [Penning & Talalay (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 4504-4508] was examined with several substrates. Most non-steroidal anti-inflammatory drugs are competitive inhibitors (e.g. Ki for indomethacin, 0.20 microM for 9,10-phenanthrenequinone reduction at pH 6.0, and 0.835 microM for androsterone oxidation at pH 7.0), except for salicylates, which act non-competitively (e.g. Ki for aspirin, 650 microM for androsterone oxidation). The inhibitory potency of these agents falls sharply as the pH is increased from 6 to 9. Most anti-inflammatory steroids are likewise competitive inhibitors, except for the most potent (betamethasone and dexamethasone), which act non-competitively. The enzyme is inhibited competitively by arachidonic acid and various prostaglandins.

3-Hydroxysteroid Dehydrogenases↗
PubMed1988

Electrophoretic and immunochemical characterization of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenases of rat tissues.

The properties of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase from Sprague-Dawley rat liver cytosol have been re-examined in light of several reports which suggest that multiple forms of the enzyme may exist in this tissue. During enzyme purification, chromatography on DE-52 cellulose and chromatofocusing columns indicated the existence of only one form of the protein. Re-chromatography of the purified enzyme by either of these techniques failed to resolve the protein into additional forms. When the purified enzyme was subjected to SDS/polyacrylamide-gel electrophoresis a single band corresponding to Mr 34,000 was detected. Two-dimensional gels showed one predominant protein with a pI of 5.9. Using the homogeneous enzyme as antigen, high-titre polyclonal antibody was raised in rabbits. Western-blot analysis of cytosolic proteins prepared from male and female Sprague-Dawley rat liver indicated the presence of a single immunoreactive band with an Mr of 34,000 in both sexes. All of the 3 alpha-hydroxysteroid dehydrogenase activity present in rat liver cytosol could be immunotitrated with the antibody and the resulting titration curve was superimposable on the titration curve obtained with the purified enzyme. Western-blot analysis of cytosolic proteins prepared from livers of male Wistar and Fischer rats also revealed the presence of a single immunoreactive protein with an Mr of 34,000. These data indicate that, contrary to previous reports, only one form of the dehydrogenase may exist in liver cytosols prepared from a variety of rat strains. Although 3 alpha-hydroxysteroid dehydrogenase activity is known to be widely distributed in male Sprague-Dawley rat tissues, Western blots indicate that only the liver, lung, testis and small intestine contain immunoreactive protein with an Mr of 34,000. The levels of immunoreactive protein in these tissues follow the distribution of dihydrodiol dehydrogenase.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects.

OBJECTIVE: Sexual dimorphism of 11 beta hydroxysteroid dehydrogenase activity (11 beta HSD) as measured by the urinary 11-OH/11-oxo cortisol metabolite ratio has been documented in healthy subjects. Since body composition, fat distribution and insulin sensitivity vary between the sexes we have investigated whether these factors may account for the observed difference. Studies were performed in ACTH deficient hypopituitary subjects to eliminate the effect of feedback modulation of cortisol secretion. DESIGN AND PATIENTS: 44 hypopituitary patients, (m:f, 32:12), median age 51 years, median weight 86 kg, on hydrocortisone and other replacement therapy as appropriate were studied. MEASUREMENT: Urine 11-OH/11-oxo cortisol metabolites and serum and urine cortisone (E) and cortisol (F) were measured in relation to total cortisol metabolites and cortisol binding globulin; fat distribution was assessed by Dual Energy X-ray absorptiometry (DXA), and insulin sensitivity by homeostatic model of assessment. RESULTS: Cortisol bioavailability (total urine cortisol metabolites, urine free cortisol and cortisol binding globulin) was similar in both sexes. The 11-OH/11-oxo ratio was lower in females than males (median; 0.99 vs 1.3, P < 0.03) while thyroid status was similar. Females had higher percentage fat (median 47.7 vs 34.9, P < 0.01); total fat (median 39.5 vs 34.9 kg, P < 0.01), android fat (median 9.1 vs 6.6 kg, P < 0.01); gynoid fat (median; 9.9 vs 6.8 kg, P < 0.05) and lower insulin sensitivity (median 15.3 vs 30.6, P < 0.01). In all subjects, the 11-OH/11-oxo ratio was inversely related to body weight (P < 0.01), % fat (P < 0.05), total fat (P < 0.01), android fat (P < 0.01), gynoid fat, (P < 0.01) and directly correlated to insulin sensitivity, P < 0.01. Stepwise regression analysis showed gynoid fat to be the most important factor determining the 11-OH/11-oxo ratio. In 24 subjects (f:m, 8:16) on exogenous sex steroid therapy insulin sensitivity was similar but the sexual dimorphism of the 11-OH/11-oxo ratio remained unchanged (median; 1.0 vs 1.7, P < 0.05). The urine and serum F and E and their ratio (F/E) were similar in these groups. CONCLUSION: These data confirm the presence of sexual dimorphism in 11 beta-hydroxysteroid dehydrogenase activity in hypopituitary patients as described in normal individuals. This is the first in vivo evidence that this dimorphism is related to body composition. Our findings suggest that sexual dimorphism may be determined by the activity of type 1 and not type 2 11 beta-hydroxysteroid dehydrogenase.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases.

We have expressed in Escherichia coli functionally active proteins encoded by two human cDNAs that were isolated previously by using rat 3 alpha-hydroxysteroid dehydrogenase cDNA as the probe. The expressed proteins catalyzed the interconversion between 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol. Therefore, we name these two enzymes type I and type II 3 alpha-hydroxysteroid dehydrogenases. The type I enzyme has a high affinity for dihydrotestosterone, whereas the type II enzyme has a low affinity for the substrate. The tissue-specific distribution of these two enzymes was determined by reverse transcription polymerase chain reaction using gene-specific oligonucleotide primers. The mRNA transcript of the type I enzyme was found only in the liver, whereas that of the type II enzyme appeared in the brain, kidney, liver, lung, placenta, and testis. The structure and sequence of the genes encoding these two 3 alpha-hydroxysteroid dehydrogenases were determined by analysis of genomic clones that were isolated from a lambda EMBL3 SP6/T7 library. The genes coding for the type I and type II enzymes were found to span approximately 20 and 16 kilobase pairs, respectively, and to consist of 9 exons of the same sizes and boundaries. The exons range in size from 77 to 223 base pairs (bp), whereas the introns range in size from 375 bp to approximately 6 kilobase pairs. The type I gene contains a TATA box that is located 27 bp upstream of multiple transcription start sites. In contrast, the type II gene contains two tandem AP2 sequences juxtaposed to a single transcription start site.

3-Hydroxysteroid Dehydrogenases↗
PubMed1999

Purification and characterization of rat liver naloxone reductase that is identical to 3alpha-hydroxysteroid dehydrogenase.

1. Rat liver cytosol produced exclusively 6beta-naloxol from naloxone in the presence of either NADPH or NADH at pH 7.4. The amount of 6beta-naloxol formed with NADPH was about four times that with NADH. The enzyme responsible for this reaction, termed naloxone reductase, was purified to a homogeneous protein by various chromatographic techniques. 2. The purified enzyme is a monomeric protein with a molecular weight of 34000 and an isoelectric point of 5.9, and it has a dual co-factor specificity for NADPH and NADH. The enzyme catalysed the reduction of various carbonyl compounds as well as naloxone analogues, and the dehydrogenation of 3alpha-hydroxysteroids and alicyclic alcohols. Indomethacin, quercetin and sulphhydryl reagents potently inhibited the enzyme, but pyrazole and barbital had no effect on the enzyme activity. 3. Identity of naloxone reductase and 3alpha-hydroxysteroid dehydrogenase in rat liver was demonstrated by comparing the elution profiles of the two enzyme activities during purification, the ratios of the two enzyme activities at each purification steps, and thermal stability and susceptibility to inhibitors for the two enzyme activities. 4. Amino acid sequences of five peptides obtained by proteolytic digestion of the purified enzyme were completely identical to the corresponding regions of previously reported 3alpha-hydroxysteroid dehydrogenase.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Characterization of a 3 alpha-hydroxysteroid dehydrogenase/carbonyl reductase from the gram-negative bacterium Comamonas testosteroni.

A new form of the NAD(P)-dependent 3 alpha-hydroxysteroid dehydrogenases (3 alpha-HSDs), present in the gram-negative bacterium Comamonas testosteroni ATCC 11996, was isolated from a testosterone-induced bacterial extract and characterized. The enzyme (HSD 28) has a monomeric molecular mass of 28 kDa. It belongs to the protein superfamily of short-chain dehydrogenases/reductases (SDR) as established by N-terminal sequence analysis. Along with the 3 alpha-hydroxysteroid dehydrogenase and 3-oxo-reductase activities towards a variety of cis or trans fused A/B ring steroids, it also reduces several xenobiotic carbonyl compounds, including a metyrapone-based class of insecticides, to the respective alcohol metabolites. No dihydrodiol dehydrogenase activity towards trans- or cis-benzene-dihydrodiols could be detected, thus distinguishing it from the indomethacine-sensitive, mammalian liver type 3 alpha-HSDs. Subcellular fractionation revealed that the enzyme is localized in the cytoplasm of the bacterial cell. Proteins similar to the 3 alpha-HSD were detected and characterized from Comamonas testosteroni strain ATCC 17454 and from a commercially available steroid-induced extract of a patent Pseudomonas strain. The N-terminal amino acid sequence of the 3 alpha-HSD from the latter strain (HSD 29) is highly similar (94% identity over 15 residues) to a previously determined primary structure of a Pseudomonas species 3 alpha-HSD. However, no similarities could be detected between HSD 28 and a recently determined 3 alpha-HSD sequence from the ATCC 11996 Comamonas strain. The specific crossreaction of antibodies directed against mammalian liver type I 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD I) with the isolated 3 alpha-HSDs suggests the existence of a functionally and structurally related subgroup within the SDR superfamily. The broad substrate specificities of the characterized 3 alpha-HSD enzymes lead to the conclusion that they might participate in the intestinal bioactivation or inactivation of hormones, bile acids and xenobiotics since Comamonas testosteroni and related species are found in the intestinal tract of vertebrates including man.

3-Hydroxysteroid Dehydrogenases↗
PubMed1995

11 beta-Hydroxysteroid dehydrogenase and its inhibitors in hypertensive pregnancy.

Preeclampsia is accompanied by amplification of the sodium retention that is a feature of normal pregnancy. Recent evidence suggests that mineralocorticoid receptor activation is increased in preeclampsia, but classic mineralocorticoids (aldosterone, 11-deoxycorticosterone) are not present in excess. Cortisol can act as a mineralocorticoid receptor agonist only when its renal inactivation to cortisone by 11 beta-hydroxy-steroid dehydrogenase is impaired, for example, in congenital enzyme deficiency and after administration of exogenous inhibitors (eg, licorice). Endogenous inhibitors of this enzyme have been detected in human urine and are increased in pregnancy. To establish whether cortisol causes mineralocorticoid excess in hypertensive pregnancy and whether endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase are responsible, we studied 25 hypertensive pregnant patients (13 with preeclampsia and 12 with gestational hypertension), 16 normotensive pregnant subjects, and 13 nonpregnant control subjects. Concentrations of plasma renin and aldosterone were increased in pregnancy, but less so in hypertensive pregnancy. Plasma potassium and urinary electrolytes were not different between the groups. Plasma cortisol was increased in pregnancy but not different in hypertensive pregnancy, and urinary cortisol, plasma and urinary cortisone, and urinary tetrahydrocortisol and tetrahydrocortisone were not different between the groups. Endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase were more active in urine from pregnant women but were not increased further in hypertensive pregnancy. There were no differences in these parameters between patients with preeclampsia and gestational hypertension. We conclude that deficient inactivation of cortisol to cortisone does not contribute to the sodium retention of normotensive or hypertensive pregnancy and that endogenous inhibitors of 11 beta-hydroxysteroid dehydrogenase have no evident pathophysiological significance in pregnancy.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

Localization of an 11 beta hydroxysteroid dehydrogenase activity to the distal nephron. Evidence for the existence of two species of dehydrogenase in the rat kidney.

An 11 beta hydroxysteroid dehydrogenase (11 beta HSD) activity has been localized in the rat kidney by a histochemical technique which links steroid metabolism with the production of a color reaction. Oxidation of 11 beta-hydroxyandrostenedione was observed in cortical distal convoluted tubules and in medullary collecting ducts. Carbenoxolone abolished staining, no reaction was obtained with androstenedione hydroxylated at the 17 or 19 position, and oxidation of 11 beta-hydroxyandrostenedione was nicotinamide-adenine dinucleotide (NAD) dependent. These results demonstrate the presence of a dehydrogenase activity separate from the nicotinamide-adenine dinucleotide phosphate (NADP)-dependent 11 beta hydroxysteroid dehydrogenase recently purified and cloned from rat liver. We have named this activity 11 beta HSD2 to distinguish it from the NADP-dependent 11 beta HSD. Histological studies showed that 11 beta HSD2 activity does not correlate with the immunocytochemical localization of the previously defined 11 beta HSD enzyme, but rather the 11 beta HSD2 activity is localized in the distal tubules of the rat kidney. In this respect 11 beta HSD2 colocalizes with the mineralocorticoid receptor. No reaction product was obtained using cortisol or corticosterone as substrate with either NAD or NADP as cofactor. Furthermore incubation of tissue sections with 11 beta androstenedione in the presence of deoxycorticosterone completely inhibited cytochemical staining. We interpret these results as evidence of 20 reductase activity which uses the reduced cofactor at the expense of the color reaction. These results support the crucial role played by an 11 beta hydroxysteroid dehydrogenase in the local protection of type I receptors in mineralocorticoid selective tissues.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Differential localization of the 5 alpha-reductase and the 3 alpha-hydroxysteroid dehydrogenase in neuronal and glial cultures.

The activities of the 5 alpha-reductase [the enzyme that converts testosterone into dihydrotestosterone (DHT)] and 3 alpha-hydroxysteroid dehydrogenase [the enzyme that converts DHT into 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha-diol)] have been evaluated in primary cultures of neurons, oligodendrocytes, and type 1 and 2 astrocytes obtained from fetal or neonatal rat brain. All cultures were used on the fifth day. The formation of DHT and 3 alpha-diol was evaluated by incubating the different cultures with [14C]testosterone or [14C]DHT as substrates. The results obtained indicate that the formation of DHT takes place preferentially in neurons; however, type 2 astrocytes and oligodendrocytes also possess considerable 5 alpha-reductase activity, while type 1 astrocytes show a much lower enzymatic activity. A completely different localization was observed for 3 alpha-hydroxysteroid dehydrogenase. The formation of 3 alpha-diol appears to be mainly, if not exclusively, present in type 1 astrocytes. 3 alpha-Diol is formed in very low yields by neurons, type 2 astrocytes and oligodendrocytes. The compartmentalization of two strictly correlated enzymes (5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase) in separate central nervous system cell populations suggests the simultaneous participation of neurons and glial cells in the 5 alpha-reductive metabolism of testosterone and possibly other hormonal steroids (e.g. progesterone, corticoids, etc.).

3-Hydroxysteroid Dehydrogenases↗
PubMed1994

Renal 11 beta-hydroxysteroid dehydrogenase activity is enhanced by ramipril and captopril.

Changes of renal 11 beta-hydroxysteroid dehydrogenase activity may contribute to variations of sodium excretion by modulating inactivation of cortisol or corticosterone and thus their access to mineralocorticoid receptors. Angiotensin-converting enzyme inhibitors enhance sodium excretion but by mechanisms still incompletely understood. To test the hypothesis that the angiotensin-converting enzyme inhibitors ramipril and captopril act in part by enhancing renal 11 beta-hydroxysteroid dehydrogenase activity, the effects of these agents in slices of rat renal outer medulla were examined. Conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone was 58% greater in tissue from fasted rats than from fed rats (mean +/- SE 2467 +/- 146 vs. 1584 +/- 102 pmol/mg protein.h, P < 0.01). Incubation of tissue from fed rats with physiological concentrations of ramiprilat, the active form of ramipril, enhanced activity (1497 +/- 76) to fasted levels (2323 +/- 120, P < 0.02). Captopril had a similar in vitro effect (1557 +/- 92 to 2109 +/- 116, P < 0.01). Ramipril given in vivo to fed rats also increased activity to fasted levels (1716 +/- 101 to 2737 +/- 396, P < 0.05). Angiotensin II incubated with renal tissue from fasted rats suppressed activity to fed levels, but this effect was prevented by the presence of ramiprilat. Both ramipril and captopril enhance renal 11 beta-hydroxysteroid dehydrogenase activity, and this effect is only partly explained by limitation of endogenous angiotensin II production.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1997

Metabolism of pravastatin sodium by 3 alpha-hydroxysteroid dehydrogenase.

When incubated with isolated rat hepatocytes, pravastatin sodium (PS) yielded a small amount of a metabolite in addition to two major metabolites that have already been reported. The previously uncharacterized metabolite was found to be formed by at first being enzymatically dehydrogenated to 6'-keto intermediate (R-104), followed by decomposition to give the aromatized metabolite (R-195), through spontaneous deesterification with accompanying aromatization. The PS-6'beta-hydroxydehydrogenase activity was localized in cytosolic fraction and required NADP, preferentially over NAD, as a cofactor. The formation of R-195 by rat liver cytosol was strongly inhibited by indomethacin, 3 alpha-hydroxysteroids (but not 3 beta-isomers) and 3-ketosteroids. The results and high substrate specificity of purified PS-6'beta-hydroxydehydrogenase toward 3 alpha-hydroxysteroids suggested that the enzyme is identical to 3 alpha-hydroxysteroid dehydrogenase.

3-Hydroxysteroid Dehydrogenases↗
PubMed1977

Histochemical distribution of delta5-3beta- and 17beta-hydroxysteroid dehydrogenases in hamster trophoblast.

The histochemical distribution of delta5-3beta- and 17beta-hydroxysteroid dehydrogenases was demonstrated in hamster trophoblast between Days 8 and 15 of pregnancy. The delta5-3beta-hydroxysteroid dehydrogenase activity in the ectoplacental trophoblast of 8-day embryos was demonstrated by use of delta5-pregnenolone and dehydroepiandrosterone as substrates; between Days 11 and 15, activity was demonstrated in the trophoblastic giant cells of the placenta and in the intra-arterial trophoblast cells when delta5-pregnenolone was the substrate. Between Days 11 and 15, 17beta-hydroxysteroid activity was present in the spongiotrophoblast, labyrinth, placental giant cells and intra-arterial trophoblast cells, as shown by use of testosterone and oestradiol as substrates. Both enzymes were demonstrated in ectopic trophoblast cells, indicating that these activities are autonomous.

17-Hydroxysteroid Dehydrogenases↗
PubMed1982

Localization of delta 5-3 beta- and 17 beta-hydroxysteroid dehydrogenase activity in the efferent ducts, epididymis and vas deferens of the rabbit, hamster and marmoset monkey.

The presence and distribution of delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD: EC 1.1.1.51) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD: EC 1.1.1.51) were studied histochemically in the excurrent ducts of the rabbit, hamster and marmoset monkey. Dehydroepiandrosterone (DHEA) and testosterone were used as substrates for delta 5-3 beta-HSD and 17 beta-HSD respectively, while phenanthroline monohydrate was used to eliminate non-specific staining due to other tissue dehydrogenases. The rabbit possessed least enzyme activity, which was confined to tubules in the middle segment of the epididymis. Enzyme activity was demonstrable throughout the excurrent ducts of the hamster and marmoset, with maximal staining occurring in the middle segment of the epididymis in both species. The region of maximum activity of hydroxysteroid dehydrogenase is where spermatozoa first develop their fertilizing capacity.

17-Hydroxysteroid Dehydrogenases↗
PubMed2000

Localization of type 1 17beta-hydroxysteroid dehydrogenase mRNA and protein in syncytiotrophoblasts and invasive cytotrophoblasts in the human term villi.

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play a key role in the synthesis of sex steroids. The hallmark of this family of enzymes is the interconversion, through their oxydoreductive reactivity at position C17, of 17-keto- and 17beta-hydroxy-steroids. Because this reaction essentially transforms steroids having low binding activity for the steroid receptor to their more potent 17beta-hydroxysteroids isoforms, it is crucial to the control of the physiological activities of both estrogens and androgens. The human placenta produces large amounts of progesterone and estrogens throughout pregnancy. The placental type 1 17beta-HSD enzyme (E17beta-HSD) catalyzes the reduction of the low activity estrogen, estrone, into the potent estrogen, estradiol. We studied the cell-specific expression of type 1 17beta-HSD in human term placental villous tissue by combining in situ hybridization to localize type 1 17beta-HSD mRNA with immunohistochemistry using an antibody against human placental lactogen, a trophoblast marker. Immunolocalization of E17beta-HSD was also performed. To ascertain whether other steroidogenic enzymes are present in the same cell type, cytochrome P450 cholesterol side-chain cleavage (P450scc), P450 aromatase, and type 1 3beta-hydroxysteroid dehydrogenase (3beta-HSD) were also localized by immunostaining. Our results showed that the syncytium is the major steroidogenic unit of the fetal term villi. In fact, type 1 17beta-HSD mRNA and protein, as well as P450scc, P450 aromatase, and 3beta-HSD immunoreactivities were found in these cells. In addition, our results revealed undoubtedly that extravillous cytotrophoblasts (CTBs), e.g. those from which cell columns of anchoring villous originate, also express the type 1 17beta-HSD gene. However, CTBs lying beneath the syncytial layer, e.g. those from which syncytiotrophoblasts develop, contained barely detectable amounts of type 1 17beta-HSD mRNA as determined by in situ hybridization. These findings, along with those from other laboratories confirm the primordial role of the syncytium in the synthesis of steroids during pregnancy. In addition, our results indicate for the first time that CTBs differentiating along the invasive pathway contain type 1 17beta-HSD mRNA.

17-Hydroxysteroid Dehydrogenases↗