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Biomedica : Revista Del Instituto... Dec 2009Few data exist with respect to the effects of androsterone and their derivatives at cardiovascular level. In addition, the molecular mechanisms and cellular site of... (Comparative Study)
Comparative Study
INTRODUCTION
Few data exist with respect to the effects of androsterone and their derivatives at cardiovascular level. In addition, the molecular mechanisms and cellular site of action of these androgens are still unclear.
OBJECTIVE
An evaluation was conducted on the effects induced by androsterone and hemisuccinate of androsterone on perfusion pressure and vascular resistance.
MATERIALS AND METHODS
The effects of both androsterone and hemisuccinate of androsterone on the perfusion pressure and vascular resistance in isolated rat hearts (Langendorff model) were evaluated.
RESULTS
The results showed that: (1) the hemisuccinate of androsterone [10(-9) M] increases the perfusion pressure and vascular resistance in comparison with the androsterone [10(-9) M]; (2) the effect of androsterone-derivative [10(-9) M-10(-5) M] on perfusion pressure not was inhibited by indometacin [10(-6) M]; (3) nifedipine [10(-6) M] blocks the effects exerted by hemisuccinate of androsterone [10(-9) M-10(-5) M] on perfusion pressure; and (4) the effect of androsterone-derivative [10(-9) M-10(-5) M] on perfusion pressure in presence of flutamide [10(-6) M] was inhibited.
CONCLUSIONS
The effects induced by androsterone and hemisuccinate of androsterone on the perfusion pressure and resistance vascular probably involve the interaction of steroid-receptor androgenic and, indirectly, activation of the calcium channel to induce variations in the perfusion pressure.
Topics: Androsterone; Animals; Blood Pressure; Calcium Channel Blockers; Calcium Channels; Coronary Vessels; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Flutamide; Heart; In Vitro Techniques; Indomethacin; Male; Nifedipine; Pregnenolone; Rats; Rats, Wistar; Vascular Resistance
PubMed: 20440461
DOI: No ID Found -
The Journal of Clinical Endocrinology... May 1985We reported previously that incubation of [3H] androsterone in homogenates of human breast tumor resulted in production of long chain fatty acid esters of androsterone...
We reported previously that incubation of [3H] androsterone in homogenates of human breast tumor resulted in production of long chain fatty acid esters of androsterone (A-LCFE). To identify the individual A-LCFE, breast tumor homogenates were incubated with androsterone, then submitted to solvent extraction, Celite chromatography, high pressure liquid chromatography and OH- negative chemical ionization mass spectrometry. The (M-1)-ions of the oleate, linoleate, palmitoleate, palmitate, arachidonate, and stearate esters of androsterone were produced. The first 3 cited unsaturated esters accounted for over 90% of the total. Since fibrocystic disease of the breast is a reported risk factor for the development of breast cancer, breast cyst fluids were analyzed for A-LCFE as part of an overall program to relate endocrine profiles in cyst fluid to the incidence of cancer. Breast cyst fluids were analyzed for total A-LCFE by a method involving solvent extraction, saponification, purification of the liberated androsterone, and then quantification of the steroid by RIA. The 10 fluids analyzed contained 0.52-3.79 ng/ml fatty acid esters, measured as androsterone. In 4 of these samples, the individual A-LCFE were analyzed by mass spectrometry. As in the incubation study, the unsaturated fatty acid esters predominated. In 3 samples, palmitoleate and in 1 sample, oleate predominated. The palmitate varied from undetectable to 25% of the total. The divergent total concentrations and profiles of A-LCFE indicate potential parameters for correlations with the subsequent course of fibrocystic disease of the breast.
Topics: Androsterone; Chromatography; Chromatography, High Pressure Liquid; Esters; Fatty Acids; Female; Fibrocystic Breast Disease; Humans; Mass Spectrometry; Radioimmunoassay
PubMed: 3980674
DOI: 10.1210/jcem-60-5-940 -
The Journal of Clinical Endocrinology... Feb 1985The metabolism of [3H]androsterone and [3H] 5 alpha-androstane-3 alpha,17 beta-diol ( [3H] 3 alpha-diol) was studied in slices of human lung tissue and cultures of human...
The metabolism of [3H]androsterone and [3H] 5 alpha-androstane-3 alpha,17 beta-diol ( [3H] 3 alpha-diol) was studied in slices of human lung tissue and cultures of human pulmonary artery endothelial cells. Lung tissue metabolized [3H]androsterone (0.25 microM) to 5 alpha-androstane-3,17-dione (30.3 pmol 100 mg-1 tissue h-1), isoandrosterone (0.7 pmol 100 mg-1 tissue h-1), 5 alpha-dihydrotestosterone (5 alpha-DHT; 0.1 pmol 100 mg-1 tissue h-1), 3 alpha-diol (0.1 pmol 100 mg-1 tissue h-1), and two polar metabolites. Pulmonary arterial endothelial cells produced the same metabolites of [3H]androsterone (0.083 microM), with the exception of the polar compounds [5 alpha-androstane-3,17-dione (1.3 pmol mg-1 protein h-1), isoandrosterone (0.1 pmol mg-1 protein h-1), 5 alpha-DHT (0.2 pmol mg-1 protein h-1), and 3 alpha-diol (0.2 pmol mg-1 protein h-1)]. Thus, the principal metabolite of [3H]androsterone in both lung tissue and endothelial cells was 5 alpha-androstane-3,17-dione. Human lung tissue metabolized [3H]3 alpha-diol (0.28 microM) to 5 alpha-DHT (8.8 pmol 100 mg-1 tissue h-1), androsterone (2.2 pmol 100 mg-1 tissue h-1), 5 alpha-androstane-3,17-dione (0.8 pmol 100 mg-1 tissue h-1), isoandrosterone (0.1 pmol 100 mg-1 tissue h-1), and four polar metabolites (0.2 pmol 100 mg-1 tissue h-1). 5 alpha-DHT was the principal metabolite of [3H]3 alpha-diol within the first hour of incubation, but the concentration of this androgen declined thereafter to 3.6 pmol 100 mg-1 tissue after 4 h of incubation. This decline was correlated with increased 5 alpha-androstane-3,17-dione synthesis (6.7 pmol 100 mg-1 tissue 4 h-1). Androsterone formation from [3H]3 alpha-diol, however, was linear with time of incubation for 4 h (8.9 pmol 100 mg-1 tissue 4 h-1). The formation of these products demonstrates that the principal 5 alpha-reduced-C19-steroid-metabolizing enzymes in human lung are 3 alpha-hydroxysteroid oxidoreductase.
Topics: Adolescent; Androstane-3,17-diol; Androstanols; Androsterone; Cells, Cultured; Endothelium; Humans; Lung; Male; Pulmonary Artery; Solvents
PubMed: 3965489
DOI: 10.1210/jcem-60-2-244 -
Wiley Interdisciplinary Reviews.... 2010The scents of mammals are complex blends of natural products that reveal a wealth of individual information. Many mammals can decipher these scent codes to discern the... (Review)
Review
The scents of mammals are complex blends of natural products that reveal a wealth of individual information. Many mammals can decipher these scent codes to discern the gender, age, endocrine status, social status, and genotype of conspecifics using dedicated sensory receptors in their olfactory system. Among these social odors are pheromones, chemicals that trigger innate behaviors and physiological responses. Here, we review classes of mammal-derived natural products that influence behavior through activation of the olfactory system.
Topics: Androsterone; Animals; Behavior, Animal; Biogenic Amines; Humans; Mammals; Models, Biological; Odorants; Olfactory Pathways; Olfactory Perception; Pheromones; Smell
PubMed: 20836008
DOI: 10.1002/wsbm.39 -
Bioorganic & Medicinal Chemistry Aug 201117Beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Δ⁴-dione) into androgen...
17Beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Δ⁴-dione) into androgen testosterone (T). To provide effective inhibitors of androgen biosynthesis, we synthesized two different series (amines and carbamates) of 3β-substituted-androsterone derivatives and we tested their inhibitory activity on 17β-HSD3. From the results of our structure-activity relationship study, we identified a series of compounds producing a strong inhibition of 17β-HSD3 overexpressed in HEK-293 cells (homogenized cells). The most active compound when tested in intact HEK-293 transfected cells, namely (3α,5α)-3-{[trans-2,5-dimethyl-4-{[2-(trifluoromethyl)phenyl] sulfonyl}piperazin-1-yl]methyl}-3-hydroxyandrostan-17-one (15b), shows an IC₅₀ value of 6 nM, this compound is thus eight times more active than our reference compound D-5-2 (IC₅₀=51 nM). This new improved inhibitor did not stimulate the proliferation of androgen-sensitive Shionogi cells, suggesting a non-androgenic profile. Compound 15b is thus a good candidate for further in vivo studies on rodents.
Topics: 17-Hydroxysteroid Dehydrogenases; Androsterone; Enzyme Inhibitors; HEK293 Cells; Humans; Inhibitory Concentration 50; Male; Prostatic Neoplasms; Structure-Activity Relationship
PubMed: 21741247
DOI: 10.1016/j.bmc.2011.06.003 -
Henry Ford Hospital Medical Journal Dec 1965
Clinical Trial
Topics: Adult; Androsterone; Anticholesteremic Agents; Butyrates; Clinical Trials as Topic; Female; Humans; Hyperlipidemias; Male; Middle Aged
PubMed: 5325188
DOI: No ID Found -
British Medical Journal Jan 1965
Topics: Androsterone; Butyrates; Clofibrate; Hypercholesterolemia; Pharmacology; Xanthomatosis
PubMed: 14218460
DOI: 10.1136/bmj.1.5427.102 -
Journal of Enzyme Inhibition and... Jun 2002A series of androsterone (ADT) derivatives substituted at position 16 were efficiently synthesized in short reaction sequences; the ether analogues were also synthesized...
Androsterone derivatives substituted at position 16: chemical synthesis, inhibition of type 3 17beta-hydroxysteroid dehydrogenase, binding affinity for steroid receptors and proliferative/antiproliferative activity on Shionogi (AR+) cells.
A series of androsterone (ADT) derivatives substituted at position 16 were efficiently synthesized in short reaction sequences; the ether analogues were also synthesized in the case of the methyl and allyl derivatives. The aim of this study was to develop inhibitors of the steroidogenic enzyme type 3 17beta-hydroxysteroid dehydrogenase and then evaluate their ability to inhibit this activity in transfected HEK-293 cells. For each compound we measured the percentage of inhibition of the transformation of 4-androstene-3,17-dione, the natural substrate of this steroidogenic enzyme, into the active androgen testosterone. The synthesized compounds proved to be weak inhibitors of this enzyme, but interestingly, these ADT derivatives do not bind to androgen, estrogen, glucocorticoid, and progestin receptors, suggesting no unsuitable receptor-mediated effects. One exception, 16alpha-(3'-bromopropyl)-5alpha-androstane-3alpha,17beta-diol, the only compound bearing a hydroxy group at position 17beta instead of a ketone, showed a strong binding affinity for the androgen receptor (70% at 1 microM) and also exhibited an antiproliferative activity on Shionogi (AR+) cells (86% at 1 microM), which was comparable to that of hydroxyflutamide, a pure antiandrogen (100% at 1 microM).
Topics: 17-Hydroxysteroid Dehydrogenases; Androsterone; Animals; Cell Division; Enzyme Inhibitors; Humans; Mice; Protein Binding; Receptors, Steroid; Structure-Activity Relationship; Transfection; Tumor Cells, Cultured
PubMed: 12443041
DOI: 10.1080/1475636021000002067 -
Endocrinology Sep 2006Farnesoid X receptor (FXR) uses bile acids as endogenous ligands. Here, we demonstrate that androsterone, a metabolic product of testosterone, is also an FXR ligand....
Farnesoid X receptor (FXR) uses bile acids as endogenous ligands. Here, we demonstrate that androsterone, a metabolic product of testosterone, is also an FXR ligand. Treatment of castrated male mice with androsterone induced expression of the FXR target gene small heterodimer partner (SHP). In mouse AML-12 hepatocytes, chenodeoxycholic acid (CDCA) or androsterone induced SHP expression with a similar kinetic pattern. The FXR antagonist guggulsterone blocked the induction of SHP by androsterone in AML-12 cells. Nuclear magnetic resonance spectroscopy demonstrated the direct binding of androsterone to purified human FXR (hFXR) ligand-binding domain (LBD) protein, resulting in the recruitment of steroid receptor coactivator protein-1 (SRC-1) coactivator peptide. In HEK293 cells, androsterone activated gal4-mouse FXR-LBD and gal4-hFXR-LBD fusion proteins, although in contrast to CDCA, androsterone activation was significantly greater for the mouse FXR-LBD than for the hFXR-LBD. Site-directed mutagenesis of the hFXR-LBD defined amino acids Asn354 and Ser345 as critical for differential species sensitivity to CDCA and androsterone, respectively. Crystal structure studies suggest that the orientation of the steroid nucleus of bile acids within the binding pocket of FXR is reversed from all other nuclear hormone receptors. In support of this model, we show here that mutations M265I or R331H, residues predicted by crystal structure to interact with the carboxylic acid tail of CDCA but not with androsterone, altered CDCA activation but had no effect on androsterone activation. Activation of FXR by androsterone may provide an additional means for physiological or pharmacological modulation of FXR.
Topics: Amino Acid Sequence; Androsterone; Animals; Cell Line; Chenodeoxycholic Acid; Crystallization; DNA-Binding Proteins; Embryo, Mammalian; Gene Expression; Hepatocytes; Histone Acetyltransferases; Humans; Kidney; Ligands; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Nuclear Receptor Coactivator 1; Orchiectomy; Pregnenediones; Receptors, Cytoplasmic and Nuclear; Recombinant Fusion Proteins; Saccharomyces cerevisiae Proteins; Structure-Activity Relationship; Testosterone; Transcription Factors
PubMed: 16675527
DOI: 10.1210/en.2005-1485 -
Canadian Journal of Physiology and... Dec 1978Androsterone sulfate (5alpha-androstan-3alpha-ol-17-one, 3-sodium sulfate) administered to freely moving rats via cerebroventricular cannulae induced analgesia, wet-dog...
Androsterone sulfate (5alpha-androstan-3alpha-ol-17-one, 3-sodium sulfate) administered to freely moving rats via cerebroventricular cannulae induced analgesia, wet-dog shakes, body jerks, rigidity, Straub tail, hypermotility, excessive grooming, hyperreactivity to stimuli, aggression, escape behavior, EEG spiking, and behavioral and EEG seizures. These responses resemble those produced by certain opiate drugs and by beta-endorphin, an endogenous peptide; they appear during the 5-min infusion period, persist in some cases for several hours, and are diminished by pretreatment with the narcotic antagonist naloxone. These findings indicate that steroid hormones can act upon at least some of the same central pathways influenced by recognized opiate compounds.
Topics: Androsterone; Animals; Behavior, Animal; Electroencephalography; Injections, Intraventricular; Male; Naloxone; Narcotics; Rats; Time Factors
PubMed: 743633
DOI: 10.1139/y78-149