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PubMed1981

Steroid transformation with immobilized microorganisms. VI. The reverse reaction of steroid-1-dehydrogenases from different micoorganisms in immobilized state.

Whole cells of Nocardia erythropolis, N. opaca and Mycobacterium phlei containing 4-en-3-oxosteroid: (acceptor)-1-en-oxidoreductase activities were immobilized by adsorption on DEAE-cellulose and silica and by entrapment in polyacrylamide gel. The obtained biocatalysts were used in an anaerobic continuous column process to transform 1,4-dien-3-oxo-steroids into 4-en-3-oxo- steroids. The half life of steroid-1(2)-reductase activity of the N. erythropolis was found to be up to 15 days. The DEAE-cellulose-adsorbed cells showed a slightly higher relative activity than free cells. The influence of substrate concentration and the action of dimethylformamide were also investigated.

Cholesterol↗
PubMed1992

Complete enzymatic deglycosylation of native sex steroid-binding protein (SBP or SHBG) of human and rabbit plasma: effect on the steroid-binding activity.

An enzymatic procedure for the complete removal of the N-linked and O-linked oligosaccharide side chains of the sex steroid-binding proteins (SBP or SHBG) of human and rabbit plasma under native conditions is described. Deglycosylation was catalyzed by N-glycanase, neuraminidase, and O-glycanase and was monitored by SDS-PAGE, lectin blotting, and molecular weight analyses by electrospray mass spectrometry. Digestion of rabbit SBP with N-glycanase generated a major 39,777-Da protein and two minor ones of 39,389 and 39,545 Da. The molecular weight of the major protein agrees with the molecular weight calculated from the sequence of the sugar-free polypeptide monomer (39,769 Da: Griffin, P.R., Kumar, S., Shabanowitz, J., Charbonneau, H., Namkung, P.C., Walsh, K.A., Hunt, D.F., & Petra, P.H., 1989, J. Biol. Chem. 264, 19066-19075), whereas the other two are deglycosylated proteolytic cleavage products lacking the TQR and TQ sequences at the amino-terminus. The N- and O-linked side chains of human SBP were removed by sequential digestion with N-glycanase and neuraminidase/O-glycanase. A 38,771-Da protein was generated, which agrees well with the molecular weight of the sugar-free polypeptide monomer (Walsh, K.A., Titani, K., Kumar, S., Hayes, R., & Petra, P.H., 1986, Biochemistry 25, 7584-7590). N-deglycosylation of human and rabbit SBP has no effect on the steroid-binding activity, but removal of the O-linked side chains of N-deglycosylated human SBP results in an apparent 50% loss of steroid-binding activity and an increase in the Kd for the binding of 5 alpha-dihydrotestosterone from 0.3 mM to 0.9 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Accumulation of glycoprotein gonadotropin in the pituitary of juvenile rainbow trout in response to androgens and C21-steroids, including 11-steroids.

Effects of steroids on the accumulation of glycoprotein gonadotropin (GTH) in pituitaries of juvenile trout were investigated by means of scanning cytophotometry applied to immunocytochemical preparations, and with the use of a radioimmunoassay. Effects on other aspects of GTH-cell activity were analyzed by measuring the size of the gonadotrops and their nuclei. Progesterone added to aquarium water and methyltestosterone incorporated into the food showed a pronounced stimulatory effect on the accumulation of GTH. To a lesser extent, treatment with cortisol, cortisone, and desoxycorticosterone acetate administered to aquarium water, and 11 beta-hydroxy-androstenedione added to the food resulted in an increase of the hypophysial content of GTH. Steroids stimulating the accumulation of GTH in the pituitary also exhibited a positive effect on GTH-cell activity as indicated by an increase in the size of gonadotropic cells. Progesterone incorporated into the food did not influence the GTH-content and the GTH-cell activity. It is suggested that the route of administration of an exogenous steroid is essential for its effect on GTH cells in trout. Comparison of GTH values reveals an excellent correlation between the data from the radioimmunoassay and those from the corresponding densitometric measurements. No correlation was observed between values of morphometrically determined GTH-cell activity and the densitometric values reflecting hypophysial GTH content.

Adrenal Cortex Hormones↗
PubMed1991

Transdermal absorption of the progestin ST-1435: therapeutic serum steroid concentrations and high excretion of the steroid in saliva.

The synthetic progestin ST-1435 was administered transdermally to six healthy women during the late luteal phase. The steroid was applied to the periumbilical area in a commercial gel ("Progestogel"), also containing progesterone. Single doses of 2.3, 4.5 and 9.0 mg of ST-1435 were given in three experiments and repeated doses of 2.3 mg of ST-1435 for five days were given in another three experiments. Samples of serum and saliva were collected and the concentrations of ST-1435 and progesterone were determined by radioimmunoassays. Transdermal absorption of the synthetic progestin ST-1435 was shown to result in serum steroid concentrations high enough for therapeutic purposes. The concentration of ST-1435 in serum was still high 24 hours after application, reflecting sustained release of the steroid from the skin. In the five-day experiments, relatively constant serum levels were achieved in different individuals, and a single dose per day seems sufficient. High excretion of ST-1435 in saliva was found two hours after gel application. However, the concentrations of serum and salivary ST-1435 were not directly correlated in different individuals. Transdermal application of ST-1435 might offer a good alternative for systemic progestin treatment.

Administration, Cutaneous↗
PubMed1982

Equilenin: a specific fluorescent probe for steroid-protein interactions in sex steroid-binding protein.

Equilenin, a naturally fluorescent steroid, has high binding affinity for human sex steroid-binding protein (SBP). At 4 degrees C the equilibrium association constant is approximately 6 X 10(7) M-1. The fluorescence excitation and emission spectra of the steroid-protein complex indicate that both hydrophobic interactions and hydrogen bonding of the 3'-hydroxyl group of the estrogen are important in its binding to the protein. Equilenin has a substantially different 3-dimensional spatial configuration compared with the normally bound androgens, and yet exhibits very tight binding to SBP. This suggests that SBP undergoes a conformational change to accomodate equilenin.

17-Ketosteroids↗
PubMed1983

Studies of the biochemical basis of steroid sulphatase deficiency--III. Phospholipid composition of microsomes from normal and steroid sulphatase deficient placentas.

The phospholipid composition has been determined for placental microsomes from 11 normal and eight pregnancies complicated by steroid sulphatase deficiency. Phosphatidylcholine, phosphatidylethanolamine and sphingomyelin were found to be the major phospholipids of normal placental microsomes, comprising respectively 41.6 +/- 4.6% (mean +/- SD). 30 +/- 5.7% and 22.5 +/- 4.9% of the total phospholipid content. There was no correlation between the steroid sulphatase activity of the microsomes and the content of any of the three phospholipids. Though their contents were significantly decreased. (P less than 0.001) phosphatidylcholine, phosphatidylethanolamine and sphingomyelin similarly constituted the major portion of the total phospholipids in sulphatase deficient microsomes, representing 36 +/- 4.2%, 34 +/- 6.1% and 22.4 +/- 6.7% respectively. Only the percentage of phosphatidylcholine was significantly different (P less than 0.02) from normal microsomes. The results show that the decreased phospholipid content of steroid sulphatase deficient placental microsomes reflects a lower content of all major classes of phospholipids, particularly phosphatidylcholine.

Female↗
PubMed1984

Identification of a non-steroidal estrogen, equol, in the urine of pregnant macaques: correlation with steroidal estrogen excretion.

Macaque urinary estrogens at late pregnancy were separated by high performance liquid chromatography and quantified, both with radioimmunoassay and an in vitro uterine estrogen receptor assay. Five estrogens were measured. Four were steroids: estriol, estrone, 17 beta-estradiol, and 16 alpha-hydroxyestrone. The fifth was a flavonoid, equol, a metabolite of plant isoflavonoids, formononetin and genistein. By mass, estrone and equol were the predominant urinary estrogens, with equol reaching levels of microgram/mg creatinine in three of 8 pregnancies studied. Both quality and quantity of urinary estrogen excretion in the rhesus (Macaca mulatta) was compared to those in 4 other species (Macaca fascicularis, Macaca nemestrina, Macaca radiata and Macaca silenus). All 5 estrogens present in the rhesus were also present in the other 4. Variability in mass of each estrogen excreted appeared no greater between species than within the rhesus. In a longitudinal study, urinary equol levels were most highly correlated with those of estrone, the predominant excretory steroid of macaque pregnancy. We conclude endogenous steroidal estrogen is related to production of equol in macaques, however, equol is not dependent on the feto-placental unit as low levels of equol were also present in male macaque urine.

Animals↗
PubMed1986

Endocrine steroid sulfotransferases: steroid alcohol sulfotransferase from human breast carcinoma cell line MCF-7.

Steroid alcohol sulfotransferase (SAS) has been isolated from the cytosol of a human breast carcinoma cell line, MCF-7. This enzyme from Sephadex G-200 chromatography displayed a mol. wt of 118 KDa. The conditions for optimal enzymic activity of SAS were determined to be 20 min incubations at 45 degrees C in 0.2 M Tris buffer (pH 7.5) containing 0.06 M Mg2+. Chromatofocusing chromatography also yielded a single peak of SAS with a pI of 5.8. Results from the incubations of a series of androstane analogues revealed that SAS required a 3 beta-hydroxyl on a steroid with the trans bridge between the A and B rings. Neither the 3 beta-allylic hydroxyl group nor the A-ring phenolic 3-hydroxyl accepted the sulfate group from 3'-phosphoadenosine-5'-phosphosulfate. D-ring beta-hydroxyl groups were tolerated by the enzyme, however, alpha-hydroxyl groups on the D-ring appeared to interfere with the reaction. Sulfurylation of steroids by SAS was related inversely to the sum of the displacements of the 3-hydroxyl plus that of the 17-hydroxyl groups relative to the plane of symmetry of the dehydroepiandrosterone nucleus. This enzyme was also capable of sulfurylating short chain aliphatic alcohols, although at greatly reduced rates. 3 beta-Chloro-5-androstene-17-one and 2-nitroestradiol. 17 beta proved to be the best inhibitors of SAS.

Breast Neoplasms↗
PubMed1987

Steroid antagonism of the hypertensinogenic activity of adrenocortical steroids.

Previous studies in sheep have provided evidence for a separate "hypertensinogenic" class of adrenocortical steroid activity which is not simply related to their classical mineralocorticoid (MC) and/or glucocorticoid (GC) actions. This study investigated the structure-activity relationships of the effects of structural analogues of prednisolone on mean arterial pressure (MAP), and MC and GC actions in sheep. Infusions of these synthetic GC at 0.6 and 24 mg/day produced variable pressor effects which were dissociated from their MC and GC actions. In other experiments, the minimum adrenocortical steroid requirement to reproduce the onset of ACTH-dependent hypertension was determined. Infusion of cortisol, aldosterone, 17 alpha-hydroxy progesterone and 17 alpha,20 alpha-dihydroxy-4-pregnene-3-one was found to be sufficient to reproduce the hypertensive response to ACTH administration in sheep. A subsequent experiment showed that substitution of cortisol by the more potent synthetic GC, prednisolone had no effect on MAP. Therefore, cortisol appears to exert an essential action in ACTH hypertension which is not dependent on its GC activity. Other studies have found that prednisolone (100 mg/day) antagonized 9 alpha-fluoro-prednisolone (0.6 mg/day) induced hypertension but not its MC effects. The effect of progesterone (500 mg/day) and the progesterone analogues, norethisterone, medroxy-progesterone and 16 alpha-methyl progesterone on ACTH (5 micrograms/kg per day) hypertension was investigated. Progesterone completely blocked the hypertension and MC effects of ACTH infusion, while medroxy-progesterone partially blocked the increase in MAP. These data support our concept of a "hypertensinogenic" class of steroid activity.

Adrenal Cortex Hormones↗
PubMed1992

Studies on anabolic steroids. 9. Tertiary sulfates of anabolic 17 alpha-methyl steroids: synthesis and rearrangement.

A simple and convenient method has been developed to prepare sulfates of anabolic 17 beta-hydroxy-17 alpha-methyl steroids. The sulfates of methandienone, 17 alpha-methyltestosterone, mestanolone, oxandrolone, and stanozolol were prepared. Different A-ring functions were not affected under the sulfation condition. The buffered hydrolyses of these sulfates provided the 17-epimers of the original steroids and 17,17-dimethyl-18-nor-13(14)-ene steroids, presumably via the 17-carbocations.

Anabolic Agents↗
PubMed1992

Receptor for sex steroid-binding protein of endometrium membranes: solubilization, partial characterization, and role of estradiol in steroid-binding protein-soluble receptor interaction.

The sex steroid-binding protein (SBP) receptor was solubilized from the membranes of human premenopausal endometrium with the zwitterionic detergent CHAPS. The binding activity of the soluble receptor was studied, allowing it to interact with [125I]SBP and precipitating the complex with polyethylene glycol 8,000. The interaction of SBP with the soluble receptor was specific, saturable, and at high affinity. Indeed, the specific binding was definitely improved on the solubilized form of the receptor. The effect exerted by sex steroids on the interaction of SBP with receptor was also examined on both the soluble and membrane-bound forms. At physiologic doses (10(-8) M) estradiol inhibits the binding at a significant extent on the soluble receptor, but not on membrane-bound form. The dose of estradiol required to significantly inhibit the SBP-specific binding was dependent on the form of receptor. In membrane-bound receptor the inhibiting dose of estradiol was higher than its physiologic concentration. Thus, it is likely that, while soluble receptor cannot recognize the complex steroid-SBP, membrane-bound receptor can interact both with "unliganded" SBP and with the estradiol-SBP complex (but not with androgen-SBP complexes) in an estrogen-dependent tissue like human endometrium.

Endometrium↗
PubMed1982

Steroid-specific and anticonvulsant interaction aspects of troleandomycin-steroid therapy.

Troleandomycin (TAO) is a macrolide antibiotic that has an apparent "steroid-sparing" effect when used in the treatment of severe steroid-dependent asthmatic patients. Recent observations demonstrated the effect of TAO on inhibiting methylprednisolone elimination, possibly contributing to its beneficial effects. Prednisolone and methylprednisolone disposition were studied before and 1 wk after initiation of TAO therapy in three patients. Methylprednisolone elimination was characteristically impaired in the presence of TAO therapy; however, there was no apparent effect on prednisolone elimination. Methylprednisolone elimination was also evaluated before and after initiation of TAO therapy in three patients receiving concomitant anticonvulsant therapy with phenobarbital-1, phenytoin-2. Methylprednisolone clearance before TAO was at least 4 times faster than normal and was probably related to enzyme induction by the anticonvulsant medication. Methylprednisolone clearance was subsequently reduced by approximately 70% in the presence of TAO therapy. The effect of TAO on corticosteroid disposition is steroid-specific and TAO can diminish the effect of certain drugs on the induction of corticosteroid metabolism.

Asthma↗
PubMed1987

The binding of fluorescent 4,6,8(14)-triene-3-one steroids to cyclodextrins as a model for steroid-protein interactions.

The 4,6,8(14)-triene-3-one steroids, highly fluorescent in aqueous solutions, lose their fluorescence power when binding occurs to hydrophobic regions of other molecules, such as the hydrophobic cavity in the ring system of cyclodextrins. The fluorescence intensity decreases almost completely when beta- and gamma-cyclodextrins are present in the solution. Scatchard plots derived from fluorescence titrations show that one or two molecules of steroid bind to one cyclodextrin molecule with KD,F-values of about 10(-4)-10(-5) mol/liter. Temperature-jump experiments show a single relaxation process, with rate constants for the decay of the beta-cyclodextrin-steroid complexes of about 10(4)-10(5) per s. For alpha- and gamma-cyclodextrins such relaxation processes are not observed.

17-alpha-Hydroxyprogesterone↗
PubMed1992

In vitro potency and selectivity of the non-steroidal androgen aromatase inhibitor CGS 16949A compared to steroidal inhibitors in the brain.

A sensitive in vitro 3H2O microassay for aromatase activity was used to evaluate the potency and selectivity of three aromatase inhibitors in mammalian (gerbil) and avian (ring dove) hypothalamus. The steroidal inhibitors, 1,4,6-androstatrien-3,17-dione (ATD) and 4-hydroxy-androstenedione (4-OH-A) were compared with a new non-steroidal imidazole inhibitor, CGS 16949A [4-(5,6,7,8-tetrahydroimidazo-[1,5-a]-pyridin-5-yl)benzonitrile HCl]. Adult male dove hypothalamic aromatase is highly active [Vmax = 5.3 pmol testosterone (T) converted/h/mg protein], has high substrate binding affinity (Km = 4.0 nM), and direct involvement in control of sexual behaviour. With [1 beta-3H]T or [1 beta-3H]A as substrate, male dove preoptic aromatase activity was inhibited more effectively and selectively by CGS 16949A. Thus, Kis and IC50s for aromatization were approximately 50 times lower for the non-steroidal inhibitor, and inhibition of the other major androgen-metabolizing enzymes (5 alpha/beta-reductase) occurred at concentrations at least one order of magnitude greater than for ATD and 4-OH-A. Neonatal male gerbil hypothalamic aromatase activity (Vmax = 1.3 pmol T converted/h/mg protein) was lower than in the dove. Aromatase inhibition by CGS 16949A is more potent in the neonatal gerbil than in the dove (Kis of 0.03 and 0.60 nM, respectively, with A as substrate). We conclude that the imidazole is an effective aromatase inhibitor in both the adult and developing brain.

Androstatrienes↗
PubMed1994

Factor-assisted DNA binding as a possible general mechanism for steroid receptors. Functional heterogeneity among activated receptor-steroid complexes.

We previously reported that activated glucocorticoid receptor-steroid complexes from rat HTC cell cytosol exist as at least two sub-populations, one of which requires a low molecular weight (700-3000 Da) factor(s) for binding to DNA. This factor is removed by Sephadex G-50 chromatography and is found predominantly in extracts of crude HTC cell nuclei. We have now determined that factor is not limited to HTC cells since an apparently identical factor(s) was found in nuclear extracts of rat kidney and liver as well as human HeLa and MCF-7 cells. Furthermore, the DNA binding of a sub-population of human glucocorticoid receptors depends on factor. While these results were obtained with agonist (dexamethasone) bound receptors, a sub-population of HTC cell receptors covalently labeled by the antiglucocorticoid dexamethasone 21-mesylate also displayed factor-dependent DNA binding. This receptor heterogeneity was not an artifact of cell-free activation since the cell-free nuclear binding of dexamethasone mesylate labeled complexes was, as in intact cells, less than that for dexamethasone bound complexes. Earlier results suggested that the increased DNA binding with factor involved a direct interaction of receptor with factor(s). We now find that the factor-induced DNA binding is retained by amino terminal truncated (42 kDa) glucocorticoid receptors from HTC cells. Thus the ability of receptor to interact with factor(s) is encoded by the DNA and/or steroid binding domains. Two dimensional gel electrophoresis analysis of dexamethasone-mesylate labeled 98 kDa receptors revealed multiple charged isoforms for both sub-populations but no differences in the amount of the various isoforms in each sub-population. Finally, activated progesterone and estrogen receptor complexes were also found to be heterogeneous, with a similar, if not identical, small molecular weight factor(s) being required for the DNA binding of one sub-population. The observations that functional heterogeneity of receptors is not unique to glucocorticoid receptors, whether bound by an agonist or antagonist, and that the factor(s) is neither species nor tissue specific suggests that factor-assisted DNA binding may be a general mechanism for all steroid receptors.

Animals↗
PubMed1996

3-Carboxy-20-keto steroids are dual uncompetitive inhibitors of human steroid 5 alpha-reductase types 1 and 2.

Steroidal 3-carboxy-20-ketones have been prepared within two structural series, the androsta-3,5-dienes and the estra-1,3,5-trienes, as potential inhibitors of types 1 and 2 steroid 5 alpha-reductase, the enzyme activity responsible for the final step in biosynthesis of dihydrotestosterone. These compounds are shown to be potent uncompetitive inhibitors of both human recombinant enzyme activities, defining a novel class of dual steroid 5 alpha-reductase inhibitors.

5-alpha Reductase Inhibitors↗
PubMed2006

Study of skeletal muscle glycogenolysis and glycolysis in chronic steroid myopathy, non-steroid histochemical type-2 fiber atrophy, and denervation.

OBJECTIVE: Muscle biopsies from chronic steroid (glucocorticoid) myopathy, non-steroid histochemical type-2 fiber atrophy, and muscle denervation patients were studied to determine if their glycogen contents, or enzymes involved in glycogenolysis and glycolysis might be related to their fiber atrophy. DESIGN AND METHODS: Fast frozen muscle biopsies from the above patients and from patients later judged by histochemistry to be normal were assayed enzymatically for glycogen content, for enzymes involved in glycogenolysis, and for 6 of the enzymes involved in glycolysis. RESULTS AND CONCLUSION: All three groups of patients had glycogen content, but only the chronic steroid myopathy muscle had statistically less glycogen content than did normal human muscle. All 3 groups had statistically low mean values compared to normal muscles for glycogen phosphorylase activity. This suggests that the biosynthesis and phosphorolysis of glycogen are not involved in muscle fiber atrophy, and glucocorticoid administration does not activate muscle glycogen biosynthesis. Histochemical type-2 fiber atrophy muscles were low compared to normal muscles in three glycogenolysis enzyme activities plus four glycolysis enzyme activities. Muscles from denervation patients were low compared to normal muscles in three glycogenolysis enzyme activities plus five glycolysis enzyme activities. This suggests that muscle denervation may lower the rate of glycolysis enough to fail to provide sufficient pyruvate for mitochondrial ATP biosynthesis, resulting in insufficient protein biosynthesis in both fiber types.

Adult↗
PubMed1989

Effect of extended use of single anabolic steroids on urinary steroid excretion and metabolism.

Long-term use of single anabolic steroids by weightlifters and body builders at dosages greater than or equal to 25 mg per 24 h resulted in reduced excretion of urinary androgen metabolites, androsterone and etiocholanolone, compared to values prior to anabolic use. The excretion of major urinary metabolites of glucocorticoids was not affected by anabolic use. Urinary excretion of anabolic steroids or anabolic metabolites averaged 20-25% of total anabolic steroid administered. The major excreted metabolites of methandrostenolone, nandrolone, oxandrolone and oxymetholone were identified by gas chromatography-mass spectrometry based on the major mass spectral ion peaks.

Anabolic Agents↗