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PubMed2000

A double-blind, placebo-controlled steroid-sparing study with budesonide Turbuhaler in Japanese oral steroid-dependent asthma patients. Japanese Pulmicort Turbuhaler study group.

OBJECTIVE: The aim of this study was to evaluate the oral steroid-sparing capacity of budesonide Turbuhaler. METHODOLOGY: One hundred and thirteen oral steroid-dependent patients were treated for 6 months with placebo or budesonide 800 microg or 1600 microg daily. Every second week the oral steroid dose was reduced if asthma control permitted. RESULTS: The reductions in oral steroid doses were 9, 35 and 60% in the placebo and budesonide 800 microg and 1600 microg groups, respectively. Oral steroid treatment could be discontinued in 4% (placebo), 15% (800 microg) and 23% (1600 microg). Mean peak expiratory flow values increased by 21 and 24 L/min in the budesonide groups but decreased by 6 L/min in the placebo group. Asthma attack, activity and sleep scores remained unchanged showing maintained efficacy. Plasma cortisol levels increased and an adrenocorticotropic hormone test showed improved adrenocortical response in both budesonide groups, indicating improved safety. Adverse drug reactions were infrequent and mild in all study groups. CONCLUSION: Budesonide Turbuhaler, 800 microg and 1600 microg daily, resulted in a significant reduction in oral steroid usage in steroid-dependent patients. The effect was achieved with maintained asthma control together with improvements in lung and adrenal functions.

Administration, Inhalation↗
PubMed2003

3Beta-sulfamate derivatives of C19 and C21 steroids bearing a t-butylbenzyl or a benzyl group: synthesis and evaluation as non-estrogenic and non-androgenic steroid sulfatase inhibitors.

A series of C19 and C21 steroids bearing one or two inhibiting groups (3beta-sulfamate and 17alpha- or 20(S)-t-butylbenzyl or benzyl) were synthesized and tested for inhibition of steroid sulfatase activity. When only a sulfamate group was added to dehydroepiandrosterone, androst-5-ene-3beta,17beta-diol, pregnenolone and 20-hydroxy-pregnenolone, no significant inhibition of steroid sulfatase occurred at concentrations of 0.3 and 3 microM. With only a t-butylbenzyl or a benzyl group, a stronger steroid sulfatase inhibition was obtained in the androst-5-ene than in the pregn-5-ene series. Comparative results from the screening tests and the IC50 values have shown that the effect of a sulfamate moiety as a second inhibiting group can be combined to the t-butylbenzyl or benzyl effect in the C19 and C21 steroid series. The 3beta-sulfamoyloxy-17alpha-t-butylbenzyl-5-androsten-17beta-ol (10) was thus found to be the most active compound with IC50 values of 46 +/- 8 and 14 +/- 1 nM, respectively for the transformations of E1S to E1 and DHEAS to DHEA. The IC50 values of compound 10 are similar to that of 17alpha-t-butylbenzyl-estradiol, which was previously reported by our group as a good steroid sulfatase reversible inhibitor, but remains higher than that of the potent inactivators estrone-3-O-sulfamate (EMATE) and 17alpha-t-butylbenzyl-EMATE. However, contrary to these two latter inhibitors, compound 10 did not induce any proliferative effect on estrogen-sensitive ZR-75-1 cells nor on androgen-sensitive Shionogi cells at concentrations tested, suggesting that this steroid sulfatase inhibitor is non estrogenic and non androgenic.

Androgens↗
PubMed2005

Comparison of caudal steroid epidural with targeted steroid placement during spinal endoscopy for chronic sciatica: a prospective, randomized, double-blind trial.

BACKGROUND: Chronic sciatica can be managed by caudal steroid epidural or by targeted steroid placement during spinal endoscopy. Spinal endoscopy is a new unproven procedure. We aimed to compare the two pain management techniques and to investigate whether the site of steroid placement within the epidural space was significant. METHODS: We randomized 60 patients with a 6-18 months history of sciatica to either targeted epidural local anaesthetic and steroid placement with a spinal endoscope or caudal epidural local anaesthetic and steroid treatment. Pre-treatment and 6-week, 3-month, and 6-month SF-MPQ and HAD scores were recorded. RESULTS: No significant differences were found between the groups for any of the measures at any time. However, there were significant differences within both groups compared with pre-treatment values. For the caudal group, significant improvements were found for descriptive pain at 6 months (P=0.031), VAS at 6 weeks (P=0.036), 3 months (P=0.026), and 6 months (P=0.003), present pain intensity (PPI) at 3 months (P=0.013) and 6 months (P=0.01); anxiety at 6 weeks (P=0.008), 3 months (P=0.004), and 6 months (P=0.001) and depression at 6 months only (P=0.037). For the epiduroscopy group there were fewer significant changes. PPI was significantly reduced at 6 weeks (P=0.004) and at 6 months (P=0.02). Anxiety was reduced at 6 months only (P=0.03). CONCLUSION: The targeted placement of epidural steroid onto the affected nerve root causing sciatica does not significantly reduce pain intensity and anxiety and depression compared with untargeted caudal epidural steroid injection. When analysed individually, both techniques benefited patients.

Adult↗
PubMed1976

Formation of 5alpha-reduced C19-steroids from progesterone in vitro by a pathway through 5alpha-reduced C21-steroids in ovaries of late prepubertal rats.

Ovarian homogenates from 10-150-day-old rats were incubated with [3H]progesterone and NADPH. Also, ovarian homogenates from 28-day-old rats were incubated for 5-180 min with either [14C]progesterone, [3H]5alpha-pregnane-3,20-dione or [14C]progesterone plus [3H]5alpha-pregnane-3,20-dione. Following incubation, radioactive metabolites were isolated, identified, and measured by column and paper chromatography, with derivative formation and recrystallizations to constant specific activity. Prepubertal ovaries (10, 20, and 28 days of age) converted 15-60% of progesterone to C21-17-hydroxysteroids and C19-steroids. At 40 and 150 days of age (postpubertal), the formation of these steroids decreased to less than 2%. At 10 and 150 days of age, the major C19-steroids formed from progesterone were androstenedione and testosterone. At 20 and 28 days of age, however, no accumulation of these C19-delta4-3ketosteroids was found (less than 0.1% of each), at which time the conversion of progesterone to 5alpha-reduced C19-steriods, such as androsterone and 5alpha-androstane-3alpha,17beta-diol, reached 30%. In ovaries of 28-day-old rats, the results from incubation studies for the detection of metabolic pathways indicated two biosynthetic pathways leading to 5alpha-reduced C19-steroids, one from progesterone via 5alpha-reduced C21 steroids, such as 3alpha-hydroxy-5alpha-pregnan-20-one and 3alpha,17alpha-dihydroxy-5alpha-pregnan-20-one, and a second via 17-hydroxyprogesterone, androstenedione, and testosterone. It seems that the active 5alpha-reduction of C19-delta4-3-ketosteroids and the formation of 5alpha-reduced C19-steroids by the pathway through 5alpha-reduced C21-steroids, are present in the ovaries of older prepubertal rats and may be the biological significance.

Androgens↗
PubMed2000

Traumatic hyphema: a critical review of the scientifically catastrophic history of steroid treatment therefore; and A report of 24 additional cases with no rebleeding after treatment with the Yasuna systemic steroid, no touch PLUS protocol.

PURPOSE: To establish a detailed history of steroid therapy administered either systemically or topically for traumatic hyphema (TH) over the past 40 years. To this literature, we report and add another 24 TH cases treated with the Yasuna systemic steroid No Touch PLUS protocol. METHODS: Review of all reports in Medline since its inception in 1966 and such reports not in Medline but retrievable by successive reference and various alternate sources. Retrospective review of charts of all cases of TH at the University of Florida from 1980-1987. Of 135 cases so retrieved, 24 were found who had received this treatment protocol properly. (Ethical, moral and liability aspects prohibited a formal comparative study of a no medical treatment control group since this is unconscionable and abusive at the present state of knowledge.) RESULTS: The historical review revealed that there is general ignorance of the salutary effect of both topical and systemic steroids in reducing the rebleed rate in TH. This is so marked that at least five experiments reported in the literature are invalidated to a variable degree because all patients, in both the experimental and control groups, had received topical steroids. Further, that the remarkable reduction in the rebleed rates for control groups of theoretically medically untreated TH, from the vicinity of 25% or more to the vicinity of 10-15% appears to be due primarily, if not solely, to this now ubiquitous administration of topical steroids in TH. In addition, in retrospect, there are also a remarkable number (at least 5) of major statistical errors in this literature and another 6 studies of outpatients in which compliance with therapy as outpatients is not even considered. Therefore at least 16 (57%) of the 28 papers reviewed have serious flaws and doubtful or uncertain results or conclusions. Of the 9 papers which lead one to wrongful conclusions, 5 are prejudicial against systemic steroid treatment (and 2 against systemic ACA treatment, and 2 against systemic TXA treatment). All but one of the nine are, as a corollary, prejudicial in favor of non medical treatment of TH. In our 24 cases studied, none suffered a rebleeding episode. CONCLUSIONS: The "continuing controversy" about medical treatment of TH is the direct result of poor science and poor scientific methods in clinical trials. Because no method has yet been devised to determine which traumatic hyphemas will rebleed, but preventing rebleeding is about all that we can do maximize the outcome, we recommend that all patients with TH receive the Yasuna systemic steroids no touch and/or PLUS protocol in addition to current conventional treatment (bed rest, hospitalization for all patients under 18 years of age)

Antifibrinolytic Agents↗
PubMed1987

Interleukin 2 synthesis in the presence of steroids: a model of steroid resistance.

In this study interleukin 2 (IL-2) synthesis by human lymphocytes in the presence and absence of prednisolone in a group of normal subjects has been assessed. An association between suppression in vitro of induced phytohaemagglutinin-blastogenesis by prednisolone and synthesis of IL-2 was found. Those subjects whose lymphocytes are identified as steroid-resistant have significantly higher IL-2 activity in the supernatants of both steroid and non-steroid treated lymphocyte cultures than steroid sensitive subjects. The addition of exogenous IL-2 was found to ablate the suppressive effects of steroids on lymphocyte blastogenesis. These results suggest that significantly greater activity of IL-2 in the culture supernatants of steroid resistant subjects may represent a mechanism for glucocorticoid resistance in vitro and help explain the relationship between increased loss of grafts and steroid resistance in renal allograft recipients.

Adult↗
PubMed2000

Steroid sex hormones for lower limb atherosclerosis.

BACKGROUND: There is accumulating evidence that steroid sex hormones have a beneficial effect on a number of risk factors for peripheral arterial disease. OBJECTIVES: The objective of this review was to determine whether exogenous steroid sex hormones are an effective treatment for patients with lower limb atherosclerosis. SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases Group trials register was searched, together with reference lists from relevant articles and reviews obtained through searches of Embase and Medline. SELECTION CRITERIA: Randomised controlled trials of steroid sex hormones in patients with lower limb atherosclerosis were selected. DATA COLLECTION AND ANALYSIS: Both reviewers extracted data and assessed trial quality independently. Whenever possible investigators were contacted to obtain information needed for the review that could not be found in published reports. MAIN RESULTS: Four trials appeared to meet the inclusion criteria, but one was excluded because of poor methodology and another is awaiting translation into English. The two remaining trials compared testosterone treatment with placebo in a total of 83 men with intermittent claudication. No trials were available which investigated the potentially beneficial effects of oestrogenic hormones in women with lower limb atherosclerosis. Testosterone therapy produced no improvement in tests of walking distance or in a variety of other objective tests for peripheral arterial disease, including venous filling time, muscle blood flow and plethysmography. The odds ratio for subjective improvement in symptoms using the combined trial results was also non-significant (odds ratio 1.28, 95% confidence interval 0.61 to 2.65). REVIEWER'S CONCLUSIONS: There is no evidence to date that short-term testosterone treatment is beneficial in male subjects with lower limb atherosclerosis. However, this might reflect limited data rather than the lack of a real effect.

Arteriosclerosis↗
PubMed1994

Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data.

To illustrate the informative value of descriptive multivariate analysis in biochemical screening, we have analyzed several data matrices relating to the binding of steroids to the estrogen, progestin, androgen, glucocorticoid and mineralocorticoid receptors in different organs and species. We first compared dendrograms of steroid hormone receptors, that were obtained by an automatic hierarchical classification analysis of the binding data, to published phylogenetic trees of nuclear receptors based on amino-acid sequence analysis. The former classification describes the affiliations among the receptors as given by the binding specificity of a population of 187 steroids in a traditional cytosol binding assay (an indirect comparison of ligand binding sites); the latter describes the affiliations among the receptors as given by a comparison of selected primary sequences involved in ligand-dependent regulation of transactivation and dimerization. A similar hierarchical classification was also performed on the binding data of 62 steroids to myometrium cytosol from different species in order to show to what extent the progesterone-binding proteins in these species are affiliated. Hierarchical clustering methods classify each type of variable (receptor or steroid) independently. In order to be able to correlate both types of variable (receptors and steroids) on single-display graphs, it is necessary to resort to correspondence factorial analysis (CFA). CFA ranks the information content within the experimental system, highlighting major correlations and disclosing secondary correlations by eliminating redundant information and background noise. This multivariate method, applied to the analysis of published data, illustrated the particular specificity of estrogen binding in human vagina and raised the question of the nature of the binding protein in this tissue. Our examples are based on small data tables that can and have been analyzed de visu. However, it is certain that such descriptive multivariate techniques are indispensable for the analysis of large data banks not only to define structure-activity relationships but to estimate the degrees of affiliation among the biological variables being measured. Knowledge of such affiliations will help to organize available information in a context where the complexity of the biological systems under study is becoming increasingly apparent.

Animals↗
PubMed1990

Steroid hormone regulation of the Achlya ambisexualis 85-kilodalton heat shock protein, a component of the Achlya steroid receptor complex.

The steroid hormone antheridiol regulates sexual development in the fungus Achlya ambisexualis. Analyses of in vivo-labeled proteins from hormone-treated cells revealed that one of the characteristic antheridiol-induced proteins appeared to be very similar to the Achyla 85-kilodalton (kDa) heat shock protein. Analysis of in vitro translation products of RNA isolated from control, heat-shocked, or hormone-treated cells demonstrated an increased accumulation of mRNA encoding a similar 85-kDa protein in both the heat-shocked and hormone-treated cells. Northern (RNA) blot analyses with a Drosophila melanogaster hsp83 probe indicated that a mRNA species of approximately 2.8 kilobases was substantially enriched in both heat-shocked and hormone-treated cells. The monoclonal antibody AC88, which recognizes the non-hormone-binding component of the Achyla steroid receptor, cross-reacted with Achlya hsp85 in cytosols from heat-shocked cells. This monoclonal antibody also recognized both the hormone-induced and heat shock-induced 85-kDa in vitro translation products. Taken together, these data suggest that similar or identical 85-kDa proteins are independently regulated by the steroid hormone antheridiol and by heat shock and that this protein is part of the Achyla steroid receptor complex. Our results demonstrate that the association of hsp90 family proteins with steroid receptors observed in mammals and birds extends also to the eucaryotic microbes and suggest that this association may have evolved early in steroid-responsive systems.

Blotting, Southern↗
PubMed2002

Genetic ablation of the steroid receptor coactivator-ubiquitin ligase, E6-AP, results in tissue-selective steroid hormone resistance and defects in reproduction.

The E6-associated protein (E6-AP), although originally identified as a ubiquitin ligase, has recently been shown to function as a coactivator of steroid receptor-dependent gene expression in in vitro assays. In order to determine whether E6-AP acts as a coactivator in vivo, physiological parameters associated with male and female sex steroid action were assessed in the E6-AP null mouse. Gonadal size was reduced in E6-AP null male and female mice in comparison to wild-type controls in conjunction with reduced fertility in both genders. Consistent with this observation, defects in sperm production and function, as well as ovulation were observed. In comparison to wild-type controls, induction of prostate gland growth induced by testosterone and uterine growth by estradiol were significantly reduced. In contrast, estrogen and progesterone-stimulated growth of virgin mammary gland was not compromised by E6-AP ablation despite E6-AP expression in this tissue. This latter finding contrasts with the impaired estrogen and progesterone-induced mammary gland development observed previously for steroid receptor coactivator type 1 (SRC-1) and SRC-3 female knockout mice. Taken together, these results are consistent with a role for E6-AP in mediating a subset of steroid hormone actions in vivo. Nevertheless, differences observed between SRC and E6-AP knockout phenotypes indicate that these two families of steroid receptor coactivators are not functionally equivalent and supports the hypothesis that coactivators contribute to tissue-specific steroid hormone action.

Animals↗
PubMed1996

Excretion of free and conjugated steroids in rainbow trout (Oncorhynchus mykiss): evidence for branchial excretion of the maturation-inducing steroid, 17,20 beta-dihydroxy-4-pregnen-3-one.

The goal of this study was to identify excretory routes of three main steroids produced by sexually mature male and female rainbow trout: 17,20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-P), sulfated 17,20 beta-P (17,20 beta-P-S), and testosterone glucuronide (TG). Spermiating males or maturing trout were cannulated via the dorsal aorta and urinary bladder and injected with tritiated steroids. Blood, water, and urine were sampled over the next 12 hr when the fish were killed and bile was collected. The identities of the excreted products were determined by anion-exchange chromatography, reverse-phase high-performance liquid chromatography, enzyme hydrolysis, acid solvolysis, microchemical modification, and thin-layer chromatography. Following the injection of tritiated 17,20 beta-P, 25% of the radioactivity rapidly appeared unmodified in the water; 15% appeared slowly in the urine, mainly as 17,20 beta-P-S; and 40% was recovered in the bile, mainly as 17,20 beta-P-glucuronide. 17,20 beta-P was shown to be released into the water via the gills. Over the 12-hr sampling period, 20% of the 17,20 beta-P released into the water was taken up again by the fish (also branchially). A mathematical analysis showed that 40% of the 17,20 beta-P would have been released into the water in the absence of uptake. Following the injection of tritiated 17,20 beta-P-S, 63% appeared very rapidly, in an unmodified form, in the urine, and 15% was recovered in the bile. Following the injection of tritiated TG, 9% appeared slowly, mainly untransformed, in the urine, and 59% was recovered in the bile. These results show that the three types of steroids are released into the water by three different routes: free steroids, gills; sulfated steroids, urine; and glucuronidated steroids, bile.

Animals↗
PubMed1995

Pre- and post-translational regulation of aromatase by steroidal and non-steroidal aromatase inhibitors.

Treatment of castrated quail with testosterone (T) reliably activates male copulatory behavior and, at the same time, increases the aromatase activity (AA), the number of aromatase-immunoreactive (ARO-ir) cells and the concentration of aromatase mRNA as measured by RT-PCR in the brain. All these effects can be mimicked by estrogens. The behavioral effects of T can be blocked by a variety of aromatase inhibitors and, in parallel, the AA is strongly inhibited in the preoptic area (POA). We showed recently that the steroidal inhibitor, 4-OH-androstenedione (OHA) markedly decreases the immunostaining density of brain ARO-ir cells while the non-steroidal inhibitor, R76713 (racemic Vorozole; VOR) unexpectedly increased the density of this staining, despite the fact that the enzyme activity was completely inhibited. To generalize these findings and try to identify the underlying mechanism, we compared here the effects of two steroidal (OHA and androstatrienedione [ATD]) and two non-steroidal (VOR and Fadrozole [FAD]) aromatase inhibitors on the aromatase immunostaining and aromatase mRNA concentration in the brain of castrated quail concurrently treated with T. The 4 inhibitors significantly blocked the activation by T of male copulation. The two steroidal inhibitors decreased the immunostaining of brain ARO-ir cells but both VOR and FAD markedly enhanced the density of this staining. In parallel, OHA and ATD completely blocked the T-induced increase in aromatase mRNA concentration, while VOR and FAD had no effect on these RNA concentrations in the POA-anterior hypothalamus and they decreased them only slightly in the posterior hypothalamus. Taken together these results suggest that the inhibition of AA by ATD or OHA and the subsequent removal of locally produced estrogens blocks the synthesis of aromatase presumably at the transcriptional level. By contrast, the two non-steroidal inhibitors tested here block AA but in parallel increase the aromatase immunostaining. This effect does not result from an enhanced transcription and it is therefore speculated that these compounds increase either the translation of the aromatase mRNA or the half-life of the protein itself.

Animals↗
PubMed2005

Analysis of anabolic steroids in the horse: development of a generic ELISA for the screening of 17alpha-alkyl anabolic steroid metabolites.

Due to the potential for misuse of a wide range of anabolic steroids in horse racing, a screening test to detect multiple compounds, via a common class of metabolites, would be a valuable forensic tool. An enzyme-linked immunosorbent assay (ELISA) has been developed to detect 17alpha-alkyl anabolic steroid metabolites in equine urine. 16beta-Hydroxymestanolone (16beta,17beta-dihydroxy-17alpha-methyl-5alpha-androstan-3-one) was synthesised in six steps from commercially available epiandrosterone (3beta-hydroxy-5alpha-androstan-17-one). Polyclonal antibodies were raised in sheep, employing mestanolone (17beta-hydroxy-17alpha-methyl-5alpha-androstan-3-one) or 16beta-hydroxymestanolone conjugated to human serum albumin, via a 3-carboxymethyloxime linker, as antigens. Antibody cross-reactivities were determined by assessing the ability of a library of 54 representative steroids to competitively bind the antibodies. Antibodies raised against 16beta-hydroxymestanolone showed excellent cross-reactivities for all of the 16beta,17beta-dihydroxy-17alpha-methyl steroids analysed and an ELISA has been developed to detect these steroid metabolites. Using this 16beta-hydroxymestanolone assay, urine samples from horses administered with stanozolol (17alpha-methyl-pyrazolo[4',3':2,3]-5alpha-androstan-17beta-ol), were analysed raw, following beta-glucuronidase hydrolysis, and following solid-phase extraction (SPE) procedures. The suppressed absorbances observed were consistent with detection of the metabolite 16beta-hydroxystanozolol. Positive screening results were confirmed by comparison with standard LCMS analyses. Antibodies raised against mestanolone were also used to develop an ELISA and this was used to detect metabolites retaining the parent D-ring structure following methandriol (17alpha-methylandrost-5-ene-3beta,17beta-diol) administration. The ELISA methods developed have application as primary screening tools for detection of new and known anabolic steroid metabolites.

Anabolic Agents↗
PubMedDate not supplied

Synthesis and steroid sulphatase inhibitory activity of C19- and C21-steroidal derivatives bearing a benzyl-inhibiting group.

Two series of compounds, benzyl alkylated at position 17alpha and 20 of androstane and pregnane, respectively, were synthesised and tested for steroid sulphatase inhibition. We compared the ability of the compounds to inhibit steroid sulphatase obtained from two different sources (homogenates of transfected HEK-293 cells and Jeg-3 cells) and with two types of substrate (DHEAS or E(1)S). The inhibitory activity of 17alpha-benzyl-5alpha-androstane-3beta,17beta-diol (7), 17alpha-benzyl-5-androstene-3beta,17beta-diol (9), 17alpha-benzyl-4,17beta-dihydroxy-4-androsten-3-one (15) and 20-benzyl-5-pregnene-3beta,20alpha-diol (16) has proven to be superior to that of danazol, the first steroid sulphatase inhibitor to be reported, but still lower than that of the potent inhibitor estrone-3-O-sulphamate. The inhibitory activity of compound 7 was as potent as that of its previously reported estrane analogue, 17alpha-benzyl estradiol. Benzyl alkylated compounds with no OH group on the A-ring (with a 4-OCH(3), 4-Cl, or 4-H and their precursor epoxides), as well as a series of basic steroids without a benzyl group (ADT, epi-ADT, 3alpha-diol, 3beta-diol, DHEA, Delta(5)-diol, DHT, T, Preg and Prog), did not show steroid sulphatase inhibition. We have thus demonstrated that the steroid sulphatase inhibitory effect of a benzyl group, previously observed for an estrane nucleus, can be extended to certain androstane and pregnane nuclei bearing a 3beta-OH or a 4-OH group. Inhibitors 7, 9, 15 and 16 did not induce any proliferative effect on androgen-sensitive Shionogi cells. However, when tested on oestrogen-sensitive ZR-75-1 cells, a proliferative effect was observed for 7 and 9, but not for 15 and 16.

Androstanes↗
PubMed1995

Starfish saponins, Part 53. A reinvestigation of the polar steroids from the starfish Oreaster reticulatus: isolation of sixteen steroidal oligoglycosides and six polyhydroxysteroids.

A reinvestigation of the starfish Oreaster reticulatus has led to the isolation of sixteen steroidal oligoglycosides and six polyhydroxysteroids. One steroidal monoglycoside has been identified as asterosaponin-1 [5], previously isolated from the same organism, and one pentaglycoside steroidal sulfate has been identified with the known ophidianoside F [1], previously isolated from starfish species of the family Ophidiasteridae. The novel pentaglycoside steroidal sulfates reticulatosides A [3] and B [4] represent the second examples of asterosaponins containing the 5 alpha-cholesta-9(11)-en-3 beta,6 alpha,20,22-tetraol aglycone. Of the remaining new steroidal oligoglycosides, the majority are characterized by the common (24S)-5 alpha-cholesta-3 beta,6 alpha,8,15 alpha,24-pentaol aglycone, with some having a sulfate group at C-6, and differing in the sugar moiety. Compounds 11, 12, 15, and 16 represent major departures from the more common structural features encountered in steroidal glycosides from starfish with the presence in 11 and 12 of a rare 5-O-methylgalactofuranosyl unit and in 15 and 16 of a 3-O-methyl-2-O-sulfate-xylopyranosyl unit. The latter was shown by nmr data combined with molecular dynamics calculations to exist in an 8:2 equilibrium mixture of the 1C4 and 4C1 conformations.

Animals↗
PubMed2003

Steroid biosynthesis in prokaryotes: identification of myxobacterial steroids and cloning of the first bacterial 2,3(S)-oxidosqualene cyclase from the myxobacterium Stigmatella aurantiaca.

Steroids, such as cholesterol, are synthesized in almost all eukaryotic cells, which use these triterpenoid lipids to control the fluidity and flexibility of their cell membranes. Bacteria rarely synthesize such tetracyclic compounds but frequently replace them with a different class of triterpenoids, the pentacyclic hopanoids. The intriguing mechanisms involved in triterpene biosynthesis have attracted much attention, resulting in extensive studies of squalene-hopene cyclase in bacteria and (S)-2,3-oxidosqualene cyclases in eukarya. Nevertheless, almost nothing is known about steroid biosynthesis in bacteria. Only three steroid-synthesizing bacterial species have been identified before this study. Here, we report on a variety of sterol-producing myxobacteria. Stigmatella aurantiaca is shown to produce cycloartenol, the well-known first cyclization product of steroid biosynthesis in plants and algae. Additionally, we describe the cloning of the first bacterial steroid biosynthesis gene, cas, encoding the cycloartenol synthase (Cas) of S. aurantiaca. Mutants of cas generated via site-directed mutagenesis do not produce the compound. They show neither growth retardation in comparison with wild type nor any increase in ethanol sensitivity. The protein encoded by cas is most similar to the Cas proteins from several plant species, indicating a close evolutionary relationship between myxobacterial and eukaryotic steroid biosynthesis.

Amino Acid Sequence↗
PubMed1965

Steroid lysis of protoplasts and effects of stabilizers and steroid antagonists.

Six synthetic antimicrobial steroids were examined for indications of their mechanism of action. Dequadin acetate, cetyl pyridinium chloride (CPC), and sodium deoxycholate were studied for comparison. Aerated cells of Sarcina lutea were washed, suspended in 1.06 M sucrose, and converted to protoplasts with 20 mug/ml of lysozyme. Lysis was measured optically at 650 mmu as a decrease in optical density. Screening tests with 50 mug/ml of each compound showed five steroids and CPC to be lytic. Protoplasts were strongly protected from lysis by pretreatment with 0.001 to 0.004 M spermine tetrahydrochloride. Other polyamines, such as spermidine phosphate, were less protective, and putrescine was ineffective. Uranyl nitrate (5 x 10(-4) M) rapidly agglutinated protoplasts and protected them from rupture by the lytic agents. Similar studies with 0.001 to 0.004 M Mg(++) showed varying degrees of protection, which, in most cases, was only temporary. Steroidal lysis did not appear to be related to chelation, since ethylenediaminetetraacetate did not cause lysis alone and antagonized some lytic compounds. Lecithin, Tween 80, Tween 20, and Span 20 at 0.05% exhibited certain effects on protoplast stability. Span 20 strongly prevented lysis by steroids. Tween 20 alone quickly caused protoplast rupture. Lecithin and Tween 80, which also caused lysis alone, interfered with lytic steroids and CPC. The test compounds were both inhibitory and lethal to cells of Sarcina lutea. The results suggest that direct action on cell membranes may be chiefly responsible for the antimicrobial properties of the steroids.

Bacteriolysis↗
PubMed1983

Dissociation of steroid binding to receptors and steroid induction of biological activity in a glucocorticoid-responsive cell.

Glucocorticoid responses in two independently derived lines of rat hepatoma tissue culture cells (HTC and FU5-5) were examined. FU5-5 cells exhibited induction of the enzyme tyrosine aminotransferase (TAT) at concentrations of dexamethasone that were approximately 7-fold lower than that required for HTC cells. FU5-5 cells also displayed substantial TAT induction with steroids that were partial agonists, or antagonists, in HTC cells. The increased sensitivity of FU5-5 cells was not, however, due to an increased affinity of FU5-5 cell receptors for dexamethasone, as determined from cell-free and whole cell binding experiments. The differential steroid sensitivity for TAT induction was observed with three other, structurally different glucocorticoids, thus apparently ruling out steroid metabolism in one of the cell lines as a cause. Also, induction of TAT in FU5-5 cells occurred at approximately 9-fold lower steroid concentrations than were required for the induction of glutamine synthetase (GS) in the same cells. Thus, the dose-response curves for TAT induction in HTC cells and for GS induction in FU5-5 cells are closely correlated with the saturation curve for whole cell steroid binding to receptor sites, while the dose-response curve for TAT induction in FU5-5 cells is shifted to lower steroid concentrations. This represents the first report of dissociation of two supposedly primary, glucocorticoid-induced functions and indicates that identical receptor-mediated processes cannot be utilized by FU5-5 cells for the induction of TAT and GS. The involvement of second messengers or different nuclear processes are possible explanations for the unusual behavior of FU5-5 cells during glucocorticoid induction of TAT.

Animals↗