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C Monder

Publications and source records attributed to C Monder.

At least 19 recordsLinked to original sources
PubMed1992

The biological activity of 7 alpha-methyl-19-nortestosterone is not amplified in male reproductive tract as is that of testosterone.

Based on the premise that testosterone, but not 7 alpha-methyl-androgens, is reduced at the 5 alpha-position in the prostate and seminal vesicles, the differential bioactivities of these androgens were investigated in castrated rats. The ability of 7 alpha-methyl-19-nortestosterone acetate (MENT) to increase the weights of ventral prostate and seminal vesicles of castrated rats was four times higher than that of testosterone, while its effect on the weights of bulbocavernosus plus levator ani muscles (muscle), was 10 times that of testosterone. MENT was also approximately 12 times more potent than testosterone in the suppression of serum gonadotropin levels. A dose of testosterone that maintains serum gonadotropin levels and muscle mass also maintains prostate and seminal vesicle weights in castrated rats. By contrast, a dose of MENT that maintains muscle and gonadotropins does not maintain prostate and seminal vesicles. The action of other 7 alpha-methylated androgens were similar to that of MENT. The importance of 5 alpha reductase in the differential action of testosterone and MENT on prostate was confirmed by using a 5 alpha-reductase inhibitor. The activity of testosterone was significantly suppressed in the ventral prostate and seminal vesicles but not on muscle by the 5 alpha-reductase inhibitor (N,N-diethyl-3-oxo-4-aza-5 alpha-androst-1-ene-17 beta-carboxamide). The enzyme inhibitor, however, had no influence on the activity of MENT on either tissue. In contrast, cyproterone acetate, an antiandrogen that competitively binds to the androgen receptors, inhibited the action of MENT and of testosterone on the prostate as well as on the muscle. In conclusion, these observations show that 7 alpha-methylated androgens can maintain muscle mass and normal gonadotropin levels in androgen deficient rats without hyperstimulating the prostate. These findings suggest that 7 alpha-methylated androgens may offer some health benefits to men who require androgen treatment.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1992

Experience with 19-nortestosterone in the therapy of systemic lupus erythematosus: worsened disease after treatment with 19-nortestosterone in men and lack of improvement in women.

Three men and 4 women with systemic lupus erythematosus (SLE) received 100 mg of 19-nortestosterone decanoate in weekly intramuscular injections over a period of 3 to 24 months. During therapy in the men plasma luteotrophic hormone and free testosterone levels decreased while estrogen levels increased. Anti-DNA antibodies also increased for unknown reasons. Serological changes in two men coincided with an overall increase in the clinical activity of SLE and the appearance of new onset Raynaud's phenomenon and pleuropericardial disease. In contrast, women treated with 19-nortestosterone showed clinical stability despite the persistence of high titer antibodies to DNA, and were able to continue therapy for as long as 16 months in one case. These data indicate that men and women with SLE respond differently to synthetic androgen therapy. Additionally, dissociation of clinical signs and symptoms from serological variables seems possible.

Adult↗
PubMed1991

Kinetic studies on rat liver 11 beta-hydroxysteroid dehydrogenase.

The kinetic behavior of homogeneous rat liver 11 beta-hydroxysteroid dehydrogenase (11-HSD) was investigated. The purified enzyme catalyzed oxidation of the 11 beta-hydroxy steroids, cortisol and corticosterone, to their 11-oxo products. The reverse 11-oxoreductase was not detected. Initial velocity studies of 11 beta-dehydrogenase were consistent with a sequential bireactant mechanism. Glycyrrhetinic acid, a competitive inhibitor of corticosterone oxidation, was uncompetitive with respect to NADP+. The observed inhibition patterns were consistent with an ordered sequential mechanism with NADP+ adding to the enzyme first. Analogs of NADP+ and NAD+ did not inhibit steroid oxidation by 11-HSD, nor did the products of the 11 beta-dehydrogenase reaction slow oxidation, or catalyze reduction. Ligand binding studies generated patterns that supported the ordered sequential mechanism derived from kinetic studies. The kinetic behavior of 11-HSD is therefore similar to other alcohol dehydrogenases. The basis for the apparent inability of homogeneous 11-HSD to catalyze reduction remains to be established.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

The human gene for 11 beta-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization.

The Type I (mineralocorticoid) receptor has identical affinities in vitro for cortisol and aldosterone. It has been suggested that the selective role of aldosterone in regulating sodium homeostasis relies on the microsomal enzyme 11 beta-hydroxysteroid dehydrogenase (11-HSD). This enzyme converts cortisol to its inactive metabolite, cortisone, preventing cortisol from binding to the Type I receptor. We have isolated human cDNA clones encoding 11-HSD from a human testis cDNA library by hybridization with a previously isolated rat 11-HSD cDNA clone. The cDNA contains an open reading frame of 876 bases, which predicts a protein of 292 amino acids. The sequence is 77% identical at the amino acid level to rat 11-HSD cDNA. The mRNA is widely expressed, but the level of expression is highest in the liver. Hybridization of the human 11-HSD cDNA to a human-hamster hybrid cell panel localized the single corresponding HSD11 gene to chromosome 1. This gene was isolated from a chromosome 1 specific library using the cDNA as a probe. HSD11 consists of 6 exons and is at least 9 kilobases long. The data developed in this study should be applicable to the study of patients with hypertension due to apparent mineralocorticoid excess, a deficiency in 11-HSD activity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

High-performance liquid chromatographic determination of cortolic and cortolonic acids as pyrenyl ester derivatives.

A new procedure is described for the detection of the acidic metabolites of cortisol (cortoic acids) as the pyrenylmethyl-21-oic esters. The derivatizing reagent, diazomethylpyrene, was prepared by an improved procedure. The reagent was used at room temperature, required no catalyst, and was not restricted by stoichiometric requirements. The steroid esters were separated by reversed-phase high-performance liquid chromatography and analyzed simultaneously by their ultraviolet absorbance and fluorescence characteristics. Identities of the products were confirmed using the photodiode array detector to determine spectral profiles, absorbance maxima, and absorbance ratios. Further confirmation of identity of the cortoic acid esters used mass spectrometry under normal and collision-activated dissociation conditions. With the method described, a linear spectral response was obtained between 8 and 1680 fmol. Application of the technique to the analysis of steroid acids in human urine indicated the presence of cortoic acids.

Chromatography, High Pressure Liquid↗
PubMed1991

Corticosteroid side-chain isomerase in the circulatory system.

Corticosteroid side-chain (CSC) isomerase catalyzes ketol-aldol interconversion of the corticosteroid side chain. The enzyme was present in the blood of mouse, rat, guinea pig, chicken, pig, horse, sheep, cow, and human. The patterns of substrate specificity, measuring 3H-1H exchange of 21-tritiated forms of 11-deoxycorticosterone, corticosterone, and cortisol, were species specific. Based on enzyme activity and immunostaining of mouse blood fractions, red blood cells had the most isomerase activity, plasma had less, and white blood cells had low but highly variable levels of enzyme. Purified mouse liver CSC isomerase was found to be adsorbed by red blood cells. The results suggest that circulating CSC isomerase is derived in part from tissue sources and is in part an intrinsic blood enzyme.

Animals↗
PubMed1991

Heterogeneity of 11 beta-hydroxysteroid dehydrogenase in rat tissues.

Using specific antisera to purified rat liver 11 beta-hydroxysteroid dehydrogenase (11-HSD), we showed that the antigen is widely distributed in rat organs. Enzyme activity and immunoreactivity generally corresponded. Highest by both criteria were liver, testis, kidney and lung. In some tissues (epididymis, pancreas and duodenum) activity was found, but antigen corresponding to 11-HSD at a Mw of 34 kDa was absent. It is suggested that these tissues have alternate enzyme forms. The 11-HSD of brain and liver were compared. Brain enzyme may control selective binding of aldosterone to Type I receptors in the hippocampus and other regions. Rat brain 11-HSD resembled that of liver or kidney in most characteristics. It differed in (a) its steroid specificity: cortisol was a good substrate for liver 11-HSD, and a poor substrate for brain enzyme; (b) stability of 11-oxoreductase (11-OR) component. Brain 11-OR was not readily inactivated; 11-OR from other tissues lost activity rapidly and spontaneously. The variations in properties of 11-HSD in specific tissues may reflect aspects of its various specific functions.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Corticosteroids, receptors, and the organ-specific functions of 11 beta-hydroxysteroid dehydrogenase.

Reversible oxidation of the biologically active corticosteroids to the inactive 11-dehydrocorticosteroids is catalyzed by 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). The properties of the enzyme based on clinical observations of individuals with defective 11 beta HSD expression, and laboratory studies of the properties and behavior of the enzyme, are consistent with separate 11 beta-dehydrogenase and 11-oxoreductase species. However, recombinant enzyme expressed in mammalian cells retain both activities, leading to the conclusion that 11 beta HSD is a unique, reversible enzyme. 11 beta HSD is present in most tissues, but its specific functions in most tissues are unknown. How the enzyme may mediate corticosteroid-receptor interaction is illustrated by studies using kidney, testis, and brain. In kidney, 11 beta HSD prevents glucocorticoids from competing inappropriately with aldosterone for mineralocorticoid receptor (MR). Lack of enzyme in humans due to natural causes or inhibition by pharmacological agents results in maximum activation of MR by glucocorticoids, leading to the clinical symptoms of apparent mineralocorticoid excess. Leydig cells of the testes synthesize testosterone, a process that is suppressed by events initiated by the binding of corticosteroid to glucocorticoid receptors (GR). Depletion of active steroid mediated by 11 beta HSD may initiate testosterone production at puberty and affect testosterone production during adult life, as for example during periods of stress. The heterogeneous distribution of MR and GR in the brain reflects the specific regional effects of glucocorticoids and mineralocorticoids on neural function. Colocalization of 11 beta HSD and corticosteroid receptors in brain may be important in controlling the specificity of corticosteroid interaction with GR and MR. The patterns of 11 beta HSD-steroid-receptor interaction illustrated with these three tissues may provide models applicable to other tissues in which corticosteroid receptors and 11 beta HSD coexist.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Regional distribution of 11 beta-hydroxysteroid dehydrogenase in rat brain.

The activity and distribution of 11 beta-hydroxysteroid dehydrogenase in rat brain is described. Oxidation of corticosterone to 11-dehydrocorticosterone was significantly increased by NADP; the reverse reaction was increased by NADPH. Cortisol was a poor substrate. Both 11-dehydrogenase (11-DH) and 11-oxoreductase (11-OR) activities were found in brains of rats from 6 days to adult, and 11-DH and 11-OR activities were positively correlated with each other. Highest enzyme activities were found in pituitary, cerebellum, hippocampus, and cortex. Lower levels were found in the olfactory region, hypothalamus, brain stem, preoptic nucleus, and amygdala. Two antisera to 11-DH, designated 56-125 and 56-126, reacted with a 34K component corresponding in mass to rat liver 11-DH on Western blots. The dominant species of protein in all brain regions reacting with rat liver 11-DH antibody 56-125, was at 26K mol wt. Antiserum 56-126 did not cross-react with the 26K protein. The 26K component was not a 34K degradation product. In each region of the brain, Western blot analysis showed that the 26K band intensity was directly proportional to enzyme activity. However, the 26K protein was devoid of 11-DH activity. All 11-DH and 11-OR activities were associated with the 34K antigen. The data demonstrate the nonuniform distribution of 11-DH in brain tissue. They are consistent with the notion that 11-DH may confer upon brain the ability to control intracellular levels of active glucocorticoids and in this way mediate steroid function within the cell.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Localization of renal 11 beta-dehydrogenase by in situ hybridization: autocrine not paracrine protector of the mineralocorticoid receptor.

In the kidney, 11 beta-dehydrogenase (11 beta-DH) converts the active steroid cortisol to inactive cortisone (corticosterone to 11-dehydrocorticosterone in the rat). In man, congenital and acquired deficiency of 11 beta-dehydrogenase are rare causes of hypertension in which cortisol acts as a potent mineralocorticoid. Observations from these clinical studies indicate that 11 beta-DH conveys specificity for the mineralocorticoid receptor in distal tubules and collecting ducts. However, while some studies do indicate 11 beta-DH activity in rat distal tubules and collecting ducts, immunohistochemical studies localize 11 beta-DH only to proximal tubules. to resolve this dilemma, we have performed in situ hybridization localization of 11 beta-DH mRNA in rat kidney tissue using 35S-labeled sense and antisense cRNA probes to rat 11 beta-DH. In contrast to our immunohistochemical studies in which 11 beta-DH protein was localized predominantly to proximal tubules in the inner cortex, 11 beta-DH mRNA was expressed in tubules in both the inner and outer cortex, most probably proximal and distal tubules, and in collecting ducts extending across the corticomedullary junction to the papillary tip. Weak hybridization was also seen in glomeruli, but no hybridization to the sense 11 beta-DH cRNA or to sections pretreated with RNase-A was observed. We conclude that renal 11 beta-DH is suitably located to prevent access of glucocorticoid to the MR in an autocrine and not a paracrine fashion. 11 beta-DH in proximal tubules may protect the glucocorticoid receptor.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

11 beta-hydroxysteroid dehydrogenase in vascular smooth muscle and heart: implications for cardiovascular responses to glucocorticoids.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in the rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. We have previously demonstrated that cortisol-induced cutaneous vasoconstriction in man is potentiated by the 11 beta-OHSD inhibitor glycyrrhetinic acid, suggesting that 11 beta-OHSD may protect vascular corticosteroid receptors. In this study we report quantitation of 11 beta-OHSD bioactivity in homogenates of rat aorta, mesenteric artery, caudal artery, and heart, expressed as the percent in vitro conversion of 3H-corticosterone to 3H-11-dehydrocorticosterone. Nicotinamide adenine dinucleotide phosphate (NADP+)-dependent 11 beta-OHSD activity was found in all of these tissues and was significantly higher in resistance vessels than aorta (P less than 0.05) [without NADP+: caudal artery (4.2 +/- 0.2%) greater than mesenteric artery (2.5 +/- 0.7%) = heart (1.67 +/- 0.2%) greater than aorta (0.79 +/- 0.2%); with 200 microM NADP+: caudal artery (43.9 +/- 2.1%) greater than heart (20.6 +/- 1.0%) = mesenteric artery (17.7 +/- 3.1%) = aorta (11.4 +/- 0.4%); heart greater than aorta]. All of these were lower than renal cortex (29.4 +/- 1.8% without NADP+; 82.4 +/- 0.4% with NADP+; P less than 0.001). 3H-11-dehydrocorticosterone was the major metabolite of 3H-corticosterone (greater than 97% of 3H-corticosterone metabolized). Reduction of 3H-11-dehydrocorticosterone to 3H-corticosterone was not detected in these experiments. We also report localization of 11 beta-OHSD-like immunoreactivity by immunohistochemistry using antisera raised against rat liver 11 beta-OHSD, and of 11 beta-OHSD messenger RNA expression by in situ hybridization using complementary RNA probes transcribed from complementary DNA encoding rat liver 11 beta-OHSD. We found 11 beta-OHSD immunoreactivity and messenger RNA expression in vascular and cardiac smooth muscle cytoplasm but not in endothelium. Thus, 11 beta-OHSD is appropriately sited to modulate access of corticosterone to vascular receptors and could influence vascular resistance, cardiac output and thereby blood pressure.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1990

Radioimmunoassay of 7 alpha-methyl-19-nortestosterone and investigation of its pharmacokinetics in animals.

A method for the measurement of 7 alpha-methyl-19-nortestosterone (7MENT) in serum/plasma by radioimmunoassay (RIA) is described. The antiserum, raised against 7 alpha-methyl-19-nortestosterone-3-O-oxime-bovine serum albumin, had a low titer (final dilution = 1:4500) and low affinity (Ka = 1.17 x 10(9) l/mol) but showed little or no cross-reactivity with several of the steroids tested. The sensitivity of the RIA was 28.2 pg/ml and the mean recovery of added cold steroid was 86 to 100%. Intra- and inter-assay coefficients of variation ranged from 4.3 to 7.3% and 7.3 to 8.4%, respectively. This RIA was used to follow plasma 7MENT levels after a single i.v. injection of the steroid in rats and rabbits. The metabolic clearance rates (MCR) of 7MENT as determined from the plasma disappearance curve for rats and rabbits were 50 l/day and 336 l/day, respectively. The MCR of 7MENT in rats and rabbits lies in the same range as for testosterone. When compared to other nortestosterone derivatives such as norethisterone, 7MENT is metabolized relatively faster.

Animals↗
PubMed1990

Purification and characterization of corticosteroid side chain isomerase.

Corticosteroid side chain isomerase of rat liver catalyzes the interconversion of the ketol (20-oxo-21-ol) and aldol (20-hydroxy-21-al) forms of the corticosteroid side chain. The enzyme has now been purified to apparent homogeneity from rat liver cytosol by sequential chromatography on anionic, hydroxylapatite, and gel filtration columns. Ketol-aldol isomerization is followed by measuring the exchange of tritium from 21-tritiated steroids with water. The native enzyme is a dimer of MW 44,000. The isoelectric point is 4.8 +/- 0.1 pH units. The purified enzyme is stimulated by Co3+ or Ni2+. The enzyme utilizes 11-deoxycorticosterone, corticosterone, and 17-deoxycortisol as substrate but not cortisol, tetrahydrocortisol, and prednisolone. Tritium-water exchange of (21S)-[21-3H]DOC is a pseudo-first-order reaction; 21-3H exchange from the 21R isomer proceeds with first-order kinetics only after a lag associated with its epimerization to the 21S form.

Amino Acids↗
PubMed1990

Corticosteroid side-chain isomerase in mouse organs: kinetic and immunologic studies.

We have investigated the distribution of corticosteroid side-chain (CSC) isomerase in the tissues of mice using as criteria its enzyme activity and immunoreactivity with monospecific polyclonal antibodies generated in rabbits. CSC isomerase was present in all organs examined. The liver and kidney contained the highest activity. The strain-dependent differences that we had previously reported for liver (i.e., BALB/c greater than C57BL/6) extended to the other organs, including the kidney, brain, heart, muscle, pancreas, testis, thymus, and lung. Western blot analysis showed a single antigen, identical in all tissues, corresponding in mobility to purified CSC isomerase. The intensities of the bands were generally proportional to enzyme activities. Titration of homogeneous enzyme with the IgG fraction of antiserum (unfractionated serum had some CSC isomerase activity) caused an increase in activity, followed by rapid inactivation after the addition of more antiserum. The broad distribution of CSC isomerase suggests that the ketol-aldol interconversion of the CSC may play a role other than, or in addition to, initiating metabolic inactivation of corticosteroids.

Animals↗
PubMed1990

Corticosteroid 11 beta-dehydrogenase of rat tissues: immunological studies.

Monospecific polyclonal antibodies to purified homogeneous rat liver corticosteroid 11 beta-dehydrogenase were generated in rabbits. The antibodies were immunoprecipitins, but enzyme activity was not completely suppressed in the antigen-antibody complex. Two antibody preparations, 56-125 and 56-126, used to detect 11 beta-dehydrogenase antigen in Western blots, generated different staining patterns for kidney, liver, brain, and heart. Using the two antibodies together, the total number of antibody-reacting components in kidney was three, and that in liver was two. Based on rates of digestion with proteases, the two prominent immunoreactive proteins in kidney appeared to be structurally or conformationally different. A prominent immunostaining component was present in stomach. Tissues that showed immunochemical evidence of 11 beta-dehydrogenase antigen showed corresponding levels of 11 beta-dehydrogenase activity. Most active were liver, testis, kidney, and lung. Lower levels of activity were found in prostate and epididymis, brain, and reproductive tract. We conclude that 11 beta-dehydrogenase is widely distributed in rat organs and is present at low levels with significant exceptions. The data indicate that 11 beta-dehydrogenase may occur in several enzyme forms, and that the distribution of these forms is to some extent tissue specific.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1990

Characterization of 11 beta-hydroxysteroid dehydrogenase gene expression: identification of multiple unique forms of messenger ribonucleic acid in the rat kidney.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11-HSD) appears to be involved in mediating aldosterone specificity of otherwise nonselective type I receptors in mineralocorticoid target tissues. In the present study gene expression of 11-HSD was characterized in various tissues of the rat by use of a complementary DNA probe coding for the rat liver 11-HSD. In the liver, lung, testis, colon, heart, hippocampus, and kidney papilla a single message was observed of length approximately 1700 nucleotides (nt). In the kidney cortex/medulla, however, messenger RNA (mRNA) species were observed at 1900 nt, 1600 nt and 1500 nt, and deadenylation studies showed that the renal 1900 nt species was heterogeneous. Northern blot analysis of 11-HSD mRNA showed low levels of expression in the kidney of the neonate and much higher levels in liver and lung with expression increasing markedly in all three tissues over development. In mature rats, a low salt diet significantly elevated 11-HSD mRNA in the liver but not in other tissues. We interpret these data as evidence for the existence of a family of 11-HSD genes, and consistent with the possibility that the hepatic species may modulate occupancy of type II (classical) glucocorticoid rather than type I receptors.

11-beta-Hydroxysteroid Dehydrogenases↗