Showing papers on "Steroid biosynthesis published in 1987"
TL;DR: The exploration of structure-activity relationships on the basis of naftifine and new synthetic strategies led to the discovery of the currently most active compound, terbinafine, the first pharmaceutical agent to contain a (E)-1, 3-enyne structural element.
Abstract: Fungal infections (mycoses) are found throughout the world. Only a few structural classes of compounds currently satisfy the demands of modern chemotherapy in their treatment; hence, the quest for new types of active substances is of major scientific and therapeutic importance. The first representative of a new class of substances–the allylamine derivatives–namely naftifine ((E)-N-methyl-N-(1-naphthylmethyl)-3-phenylallylamine) was discovered by accident and has recently become commercially available as a topical antimycotic. The exploration of structure-activity relationships on the basis of naftifine and new synthetic strategies led to the discovery of the currently most active compound of this type, terbinafine, the first pharmaceutical agent to contain a (E)-1, 3-enyne structural element. Terbinafine exhibits considerably higher activity than the original “lead” structure naftifine both in vitro and in vivo; it is also up to one order of magnitude more effective than standard preparations in various chemotherapeutic animal tests after topical or oral administration. According to clinical experience gained so far, terbinafine is well tolerated and shows promising activity against various types of mycoses. Allylamines act as potent, selective inhibitors of fungal squalene epoxidase via a novel mechanism, which, unlike in the case of other inhibitors of steroid biosynthesis, does not depend on cytochrome P450.
203 citations
TL;DR: In this article, the effects of cyclic nucleotide analogues on a clonal strain of cultured murine Leydig tumor cells (designated MA-10) were investigated, and it was shown that (Sp)-cAMPS activates and (Rp)-cAMPPS inhibits the isolated cAMP-dependent protein kinase of the Ma-10 cells.
86 citations
TL;DR: The seminal vesicle of the African catfish consists of 36–44 fingerlike lobes built up of tubules in which a fluid is secreted containing acid polysaccharides, acid-, neutral- and basic proteins, and phospholipids, which immobilizes the sperm cells and prolongs the period of sperm activity.
Abstract: The seminal vesicle of the African catfish, Clarias gariepinus, consists of 36–44 fingerlike lobes built up of tubules in which a fluid is secreted containing acid polysaccharides, acid-, neutral- and basic proteins, and phospholipids. In this fluid sperm cells are stored. The seminal vesicle fluid immobilizes the sperm cells. After ejaculation, it prolongs the period of sperm activity. The seminal vesicle fluid is secreted by the epithelium lining the tubules. The tubules in the proximal part of the lobes are predominantly lined by a simple cylindrical and those of the distal part by a simple squamous epithelium. These epithelial cells contain enzymes involved in energy-liberating processes, the enzyme activites being proportional to the height of the cells. Interstitial cells between the tubules have enzyme-histochemical and ultrastructural features indicative of steroid biosynthesis. Similar characteristics are found in testicular interstitial cells. The most rostral seminal vesicle lobes and the most caudal testicular efferent tubules form a network of tubules that opens at the point where the paired parts of the sperm ducts fuse with each other. The tubules of most seminal vesicle lobes, however, form a complex system that fuses with the unpaired part of the sperm duct.
70 citations
TL;DR: The results show that mEGF activates steroidogenesis without affecting cAMP levels and modulates the activation of steroidogenesis by the cAMP second messenger system.
48 citations
TL;DR: The reagents used for affinity labeling are analogs of hormones which produce active site-directed irreversible inhibition in the proteins which they attack, and they have been regarded as potential new drugs for controlling fertility, treating endocrine disorders, and for treating hormone-sensitive cancers.
Abstract: AFFINITY labeling for studying the amino acid topography of specific binding sites in biologically important proteins has emerged as an important biochemical technique during the past three decades. Hormone-specific proteins have been the subjects of affinity labeling during the past two decades, beginning with the analysis of the amino acids which constitute the catalytically active site of the enzymes involved in steroid biosynthesis. More recently, hormone-specific receptor and transport proteins have been characterized, and the amino acid compositions of their binding sites have been described by affinity labeling. The reagents used for affinity labeling are analogs of hormones which produce active site-directed irreversible inhibition in the proteins which they attack. Therefore, they have been regarded as potential new drugs for controlling fertility, treating endocrine disorders, and for treating hormone-sensitive cancers. The three major categories of affinity labeling hormone analogs have been cl...
48 citations
01 Jan 1987
TL;DR: The surge of interest in comparative endocrinology over the last thirty years has advanced the authors' knowledge of gonadal steroidogenesis in nonmammalian vertebrates, and the last decade has seen major advances thanks to the isolation and characterization of various compounds and the advent of more sensitive methods for hormone measurement.
Abstract: The surge of interest in comparative endocrinology over the last thirty years has advanced our knowledge of gonadal steroidogenesis in nonmammalian vertebrates. In particular, the last decade has seen major advances thanks to the isolation and characterization of various compounds and the advent of more sensitive methods for hormone measurement.
38 citations
TL;DR: Hemolymph components at this concentration or below may be affected by specific antibodies directed against them and this assay may be used to evaluate the potential for controlling other hematophagous arthropods with IgG against their hemolymph component.
Abstract: present in the hemolymph of replete females only at 10-8 M. Thus, hemolymph components at this concentration or below may be affected by specific antibodies directed against them. The main advantage of using ELISA for detection of host antibodies in the hemolymph of ticks was the small volume of hemolymph required (about 0.2 Al/tick). Thus, all adult ticks and most nymphs can be tested individually with this assay. This assay may be used to evaluate the potential for controlling other hematophagous arthropods with IgG against their hemolymph components.
34 citations
TL;DR: The results suggest that differences at a very early stage of the adrenal steroidogenesis may influence calcium homeostasis in the post-menopausal woman.
32 citations
TL;DR: It is suggested that spaceflight alters hepatic metabolism of several classes of compounds, including cholesterol, glycogen, liver lipids, and hepatic enzymes of cholesterol, glycerolipid and sphingoipid biosynthesis, and other enzyme activities.
Abstract: The inclusion of rats aboard Spacelab 3 (SL-3) allowed analyses of liver lipids, glycogen, hepatic enzymes of cholesterol, glycerolipid and sphingolipid biosynthesis, and other enzyme activities. Glycogen content was markedly elevated in livers from the flight animals compared with controls. Cholesterol was 24% (P less than 0.04) lower in livers from the experimental groups, whereas blood cholesterol was 19% higher (P less than 0.05). The activity of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of steroid biosynthesis, was 80% lower (P less than 0.01). Total phospholipids and sphingolipid levels did not differ significantly. The specific activity of fatty acyl-CoA synthetase, which is responsible for activation of fatty acids, was 37% (P less than 0.05) higher in microsomes from the rats on SL-3; however, since these animals had 25% less microsomal protein (P less than 0.02), there was no difference per gram of liver. The initial enzymes of sphingolipid and glycerolipid biosynthesis were assayed; serine palmitoyltransferase was 40% lower (P less than 0.01), and glycerol 3-phosphate acyltransferase did not differ. Hepatic cytochrome P-450 content decreased by 50% after spaceflight. Enzymes that did not differ significantly between the two groups include cytochrome b5, glutathione S-transferase, tyrosine aminotransferase, aspartate aminotransferase, and cystathionase. These findings suggest that spaceflight alters hepatic metabolism of several classes of compounds.
28 citations
01 Jan 1987
TL;DR: Disorders of carbohydrate metabolism, D.A.B. Dunger and J.J. Nicholls inherited disorders of steroid biosynthesis, G.M. Turnbull purine and pyrimidine disorders, H.H. Turnbull and N.P. Slater.
Abstract: Disorders of carbohydrate metabolism, D.B. Dunger and J.B. Holton amino acid disorders, R.J. Pollitt disorders of organic acid metabolism, R.A. Chalmers lysosomal storage disorders, C.A. Pennock peroxisomal disorders, R.B.H. Schutgens and R.J.A. Wanders defects of the mitochondrial respiratory chain, L.A. Bindoff and D.M. Turnbull purine and pyrimidine disorders, H.A. Simmonds the prophyrias, G.H. Elder collagen disorders, A.C. Nicholls inherited disorders of steroid biosynthesis, G.M. Addison lipid disorders, C.H. Bolton metal disorders, P.J. Aggett red cell disorders, A.J. Grimes and N.G.P. Slater.
24 citations
TL;DR: The enzymatic reactions involved in the conversion of [14C]cholesterol to B occurred under aerobic conditions, required the presence of an exogenous NADPH-generating system, and had identical subcellular localization in the whale adrenals.
Book•
01 Jun 1987
TL;DR: This work presents evidence for Intratesticular Factors Which Mediate the Response of Leydig Cells to Disruption of Spermatogenesis, and the Orchestration of Parturition: Does the Fetus play the Tune?
Abstract: Section I: Hypothalamus and Other Brain Areas.- Estrogen Acting on Hypothalamic Neurons May Have Trophic Effects on Those Neurons and the Cells on Which They Synapse.- Gonadal Steroid Control of Synaptogenesis in the Neuroendocrine Brain.- The Electrophysiology of the Hypothalamic Gonadotropic Hormone Releasing Hormone (GnRH) Pulse Generator in the Rhesus Monkey.- Ovarian Feedback Regulation of Gonadotropin-Releasing Hormone Secretion and Action.- Short and Ultrashort Feedback Control of Gonadotropin Secretion.- The Hypothalamo-Pituitary-Gonadal System: Role of Peptides and Sex Steroids.- Involvement of GABA in the Neuroendocrinology of Reproduction.- Section II: Pituitary.- Hypothalamic Biogenic Amines and the Regulation of Luteinizing Hormone Release in the Rat.- Dual Action of Norepinephrine in the Control of Gonadotropin Release.- Physiological and Biochemical Dissection of Mechanisms Underlying Puberty.- Biological Activity on Non-GnRH Synthetic Peptide Sequences of the GnRH Precursor.- Mechanisms of GnRH Action: Interactions between GnRH-Stimulated Calcium-Phospholipid Pathways Mediating Gonadotropin Secretion.- Phosphoinositide Turnover, Ca2+ Mobilization, and Protein Kinase C Activation in GnRH Action on Pituitary Gonadotropin Release.- Section III: Gonads.- The Ovarian Granulosa Cell as a Follicle-Stimulating Hormone Target Tissue.- Intra-ovarian Actions of Steroids in the Regulation of Follicular Steroid Biosynthesis.- Interaction between the Oocyte and the Granulosa Cells in the Preovulatory Follicle.- Secretion of Oxytocin by the Corpus Luteum and its Role in Luteolysis in the Sheep.- Catecholamine Effects on Leydig Cell Steroidogenesis: A Review.- Evidence for Intratesticular Factors Which Mediate the Response of Leydig Cells to Disruption of Spermatogenesis.- hCG/LH-Induced Changes in Testicular Blood Flow, Microcirculation and Vascular Permeability in Adult Rats.- Morphology of Normal and Abnormal Testicular Descent and the Regulation of This Process.- Section IV: Fetus and Placenta.- Sex Differentiation.- The Placental Lactogen Gene Family: Structure and Regulation.- Hormonal Influences on Fetal and Perinatal Water Metabolism.- The Orchestration of Parturition: Does the Fetus play the Tune?.- Author Index.
TL;DR: Less efficient steroidogenesis by adrenal carcinomas is suggested, a finding which may explain the large size of these tumors when the symptoms of hypercortisolism first appear.
Abstract: Patients with adrenal tumors present with varied clinical features which may be related to differing patterns of adrenal steroidogenesis. To explore the mechanism underlying these differences, we studied the in vitro activities of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17-hydroxylase (17-OH), 21-hydroxylase (21-OH), and 17-20 desmolase (17, 20-D) in 6 adrenal tumors, 4 adenomas and 2 carcinomas. Normal human adrenal tissue was also studied for comparison. Adrenal adenomas had increased 21-OH activity compared with normal adrenal tissue (11.4 +/- 0.7 vs 5.5 +/- 0.5 nmol/mg prot/min, P less than 0.002) and with adrenal carcinomas (11.4 +/- 0.7 vs 3.3 +/- 0.9 nmol/mg prot/min, P less than 0.001). Carcinomas had reduced 3 beta-HSD, 17-OH and 17,20-D activities when compared to controls, but this did not reach statistical significance. These observations suggest less efficient steroidogenesis by adrenal carcinomas, a finding which may explain the large size of these tumors when the symptoms of hypercortisolism first appear.
TL;DR: It is concluded that the two tests are suitable for confirming or excluding 5 alpha-reductase deficiency in prepubertal children, in whom basal DHT is too low for evaluation, but that physiological age-related changes in 5alpha- reductase activity have to be taken into consideration.
Abstract: Plasma testosterone (T, nmol/l) and dihydrotestosterone (DTH, nmol/l) were measured in 54 children and young adults with male pseudohermaphroditism (46XY, no defect of steroid biosynthesis) 4 h after im injection of testosterone propionate (25 mg/m2, group 1, N = 18), or before and 2, 4 and 6 days after hCG (5000 IU/m2 im, group 2, N = 36). The response to hCG was also studied in 5 control children (unilateral cryptorchidism, group 3) and that to testosterone propionate in a gonadectomized child with confirmed 5 alpha-reductase deficiency. Mean T (133.1 +/- 14.0, SEM) and DHT (17.1 +/- 2.6) in group 1 were higher than in group 2 (17.3 +/- 2.1 and 2.9 +/- 0.4), but there was not significant difference in the T/DHT ratios (group 1: 10.7 +/- 2.0; group 2: 7.2 +/- 0.6). Following testosterone-propionate, there was a negative correlation of T with age (r = -0.723). After hCG, T and DHT were lower in the prepubertal children than in those under 2 or over 10 years, and the T/DHT-ratio rose with age. Two children from group 1 had a T/DHT-ratio above 18, but urinary aetiocholanolone/androsterone (Ae/A) ratios were normal. In the child with 5 alpha-reductase deficiency, the T/DHT ratio was 60, and the urinary Ae/A ratio high. We concluded that the two tests are suitable for confirming or excluding 5 alpha-reductase deficiency in prepubertal children, in whom basal DHT is too low for evaluation, but that physiological age-related changes in 5 alpha-reductase activity have to be taken into consideration.
TL;DR: It was found that rat and rabbit testis can utilise 23,24-dinor-5-cholen-3 beta-ol to produce testosterone and the tritium/carbon-14 ratios in the testosterone and androstenedione isolated indicated that these tissues differentiated between the two substrates.
TL;DR: The results indicate that the effects of R 8110 on steroid biosynthesis in dogs are less pronounced than those of etomidate and are largely limited to a temporary inhibition of the 11 beta-hydroxylase in the adrenal gland.
Abstract: R 8110, an imidazole derivative, was shown to be clinically superior to etomidate for induction and maintenance of anaesthesia in dogs. The present study compared the effects of intravenous (i.v.) R 8110, etomidate and Ringer solution on cortisol biosynthesis by the adrenal gland in seven male labradors. A tetracosactide challenge was carried out 30 min after the i.v. injection of 3 mg/kg of both drugs and after i.v. Ringer solution (1 ml/kg). Etomidate and R 8110 both suppressed the cortisol response to tetracosactide almost completely and increased the plasma 11 beta-deoxycortisol levels more than 20 fold. Maximal 11 beta-deoxycortisol values were reached 120 min after R 8110, and not less than 300 min after etomidate. Plasma 17 alpha-hydroxyprogesterone and testosterone concentrations did not differ between placebo and R 8110 treatment, but they decreased after etomidate. These results indicate that the effects of R 8110 on steroid biosynthesis in dogs are less pronounced than those of etomidate and are largely limited to a temporary inhibition of the 11 beta-hydroxylase in the adrenal gland.
TL;DR: The analysis of 24-h excretion profiles of urinary steroids in 18 patients suffering from Cushing's syndrome or adrenocortical tumors revealed typical patterns when compared to 37 healthy control persons, 24 patients with obesity, and 6 patients with hirsutism as discussed by the authors.
Abstract: The analysis of 24-h excretion profiles of urinary steroids in 18 patients suffering from Cushing's syndrome or adrenocortical tumors revealed typical patterns when compared to 37 healthy control persons, 24 patients with obesity, and 6 patients with hirsutism. The validation of eight criteria — increased excretion of free cortisol, 6β-hydroxycortisol, 20α-dihydrocortisol, 11β-hydroxyandrosterone, and 3β-hydroxy-5-en steroids, decreased ratio of tetrahydrocortisone (THE) to tetrahydrocortisol (THF), and increased ratios of THF to allotetrahydrocortisol (a-THF) and metabolites of androgens (AM) to metabolites of cortisol (CM) — afforded reliable detection of disorders in steroid biosynthesis. The analysis of urinary steroid profiles can therefore be recommended as a screening procedure in patients with clinical symptoms of disorders in steroid production and/or metabolism.
TL;DR: It is concluded that the inhibitory effect of etomidate on steroid biosynthesis can be explained on the basis of an interaction of the drug with adrenocortical enzymes without the involvement of hypothalamic or hypophyseal mechanisms.
Abstract: A method for focal dialysis of the adrenal cortex is introduced allowing determination of adrenal steroid local release rates in conscious, freely moving rats. Etomidate, an anaesthetic drug known to interfere with adrenal steroid synthesis, blocks not only corticosterone but also aldosterone and, to a lesser degree, progesterone release. Intra-adrenal application of the drug via the dialysis system for a defined time resulted in low release rates of corticosterone without inducing sedation of the animals or even anaesthesia. Remaining low steroid concentrations during the next 5 h after cessation of the dialysis with drug-containing medium indicate that the inhibition of steroid synthesis lasted for several hours. It is concluded that the inhibitory effect of etomidate on steroid biosynthesis can be explained on the basis of an interaction of the drug with adrenocortical enzymes without the involvement of hypothalamic or hypophyseal mechanisms.
01 Jan 1987
TL;DR: The follicle is the principal functional unit of the mammalian ovary, the primary function of which is the production and release of a mature oocyte at the culmination of each ovarian cycle.
Abstract: The follicle is the principal functional unit of the mammalian ovary, the primary function of which is the production and release of a mature oocyte at the culmination of each ovarian cycle. A secondary role of the follicle is the biosynthesis and secretion of a group of steroid hormones which serve many important functions in regulation of peripheral (i. e extra-ovarian) cells and tissues.
TL;DR: Newborn rat adrenal cells in primary culture produce corticosteroid hormones and (20S)-20 alpha-reduced progesterone metabolites in amounts which depend on ACTH concentrations and stimulation time, modified by ACTH stimulation of the cultured cells.
Journal Article•
TL;DR: The present study was undertaken to investigate whether the enzymic action of 3 beta-HSD and 20 alpha- HSD could be directly stimulated by hCG and/or PRL and found that under certain experimental conditions, PRL enhanced the stimulatory effect of hCG on 3BetaHSD.
Abstract: The stimulatory effect of gonadotropins on steroid hormone production by the ovary is generally considered to be the result of an activation of the cholesterol side chain cleaving enzyme. The present study was undertaken to investigate whether the enzymic action of 3 beta-HSD and 20 alpha-HSD could be directly stimulated by hCG and/or PRL. Female immature rats were used. The ovaries were stimulated by PMSG injection to allow uniform growth of the follicles. The effect of hCG was evaluated both in in vivo and in vitro studies. The 3 beta-HSD activity in the ovarian tissue homogenate or dispersed cells was estimated from the rate of conversion of 14C-pregnenolone to 14C-progesterone in an in vitro incubation experiment. The activity of 20 alpha-HSD was measured by the conversion rate of 14C-progesterone to 14C-20 alpha-hydroxy-4-pregnen-3-one, hCG apparently stimulated the 3 beta-HSD activity both in vivo and in vitro. Under certain experimental conditions, PRL enhanced the stimulatory effect of hCG on 3 beta-HSD. Both hCG and PRL stimulated the 20 alpha-HSD activity. Intrinsic steroids, such as estrogens, androgens, and 20 alpha-hydroxy-4-pregnen-3-one, a major progestin in rodents, in the synthesis of steroid hormones was its inhibitory effect upon 3 beta-HSD.
Journal Article•