Biosynthèse des hormones stéroïdes

Summary The different pathways of biosynthesis are described, by which steroid hormones are producedin vivo in the gonads, the adrenal cortex and the placenta, orin vitro by corresponding tissue preparations. First of all a short outline of the origin of cholesterol from acetyl coenzyme A through the biological isoprene unit, the pyrophosphate of ³-iso-pentenol, through squalene, lanosterol and zymosterol is given. Partial side-chain degradation of cholesterol, where ACTH plays an important role, leads to pregnenolone and further to progesterone.The latter compounds are the starting material for the other steroid hormones. On the one hand, they are converted in the gonads and adrenals into 17-hydroxy derivatives, in which the side chain is completely removed by enzymes of the said and also of non-endocrine tissues, to form the androgens. Furthermore the adrenals produce their own typical androgens. After hydroxylation of the angular 19-methyl group, androgens are aromatised to estrogens.On the other hand, the adrenal converts progesterone by hydroxylation in 21- and, depending on the case, also in 11- and/or 17-position into the classical adrenocortical hormones. The special feature of an 18-hydroxylation and -dehydrogenation forms part of the biogenesis of aldosterone; a new example is given for the methods used towards its elucidation, consisting in the biosynthetic conversion of progesterone into two virtual intermediates, 18-oxo-progesterone and 21-desoxyaldosterone, which already contain the 18-aldehyde group, characteristic for aldosterone.The regulation of the biogenesis of the different hormones is mentioned and compounds are discussed which block one or other of the biosynthetic steps.

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D'après une conférence faite aux VIes Journées biochimiques latines, Genève (Suisse), 25 mai 1961.

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Publication No. 179Über Steroide. Communication No. 178 voirK. Heusler, P. Wieland etA. Wettstein, Helv. chim. Acta, sous presse.     

Über den Stoffwechsel der Nebennierenrindenhormone

Summary Three reactions, the 11- and the 21-hydroxylation as well as the oxydation of the angular carbon 18, are specific for the adrenals. All other enzymatic steps in the biosynthesis of steroidhormones have been demonstrated in some other tissues also. Cofactors for the hydroxylation of steroids are reduced pyridinenucleotides. They seem to be necessary to activate molecular oxygen.The extra-adrenal metabolism of adrenal hormones occurs mainly in the liver. Four principal reactions are known: the reduction of the ⁴-3-on-, the 11-keto-, and the 20-keto-group as well as the conjugation of steroids with glucuronid acid. Evidence is given that the liver is the main target of corticosteroid action.     

Adipokinetic hormones: cell and molecular biology

Adipokinetic hormones AKH I (pGlu-Leu-Asn-Phe-Thr-Pro-Asn-Trp-Gly-Thr-NH₂) and AKH II (pGlu-Leu-Asn-Phe-Ser-Trp-Gly-Thr-NH₂) are synthesized by neurosecretory cells (NSC) of the corpora cardiaca (CC) in the locust,Schistocerca gregaria. These NSC constitute a homogeneous peptide factory as each cell synthesizes both AKH I and AKH II. This homogeneity makes the CC an excellent system in which to study aspects of neuropeptide biosynthesis. This report summarizes recent findings on AKH inactivation and metabolism, as well as on AKH prohormone processing and biosynthesis.     

Hormonal induction of steroid sulphatase in the mouse

Summary By comparing steroid sulphatase levels per se, and also ratios to -galactosidase, in 6 sets of mice — normal females, entire and castrated males both with and without exogenous testosterone administration — we obtained support for the contention that induction of this enzyme is in part controlled by male hormones.     

Insect hormones in vertebrates: Anabolic effects of 20-hydroxyecdysone in Japanese quail

Ecdysteroids are hormones controlling cell proliferation, growth and the developmental cycles of insects and other invertebrates¹. They are occasionally present in various unrelated plants for no apparent reason; no phytohormonal function has yet been identified. In certain cases, ecdysteroids are accumulated to high levels in leaves, roots or seeds. Some ecdysteroid-containing plants have been known as medicinal plants for centuries. One of them,Leuzea carthamoides Iljin (Asteraceae), growing in Central Asia, contains 0.4% ecdysteroid in dry roots and 2% in seeds. A pharmacological preparation from this plant, Ecdisten, is already available as a commercial preparation for its anabolic, tonic and other effects, for medical use (review²). It remained problematic, however, whether ecdysteroids were truly responsible for these effects, becauseLeuzea contains a number of other biologically active compounds in addition to ecdysteroids. We extracted and purified ecdysteroids from the seeds ofLeuzea. With 6 g of 96% 20-hydroxyecdysone (20E), we made a large-scale feeding assay with Japanese quail to find out whether ecdysteroid alone could duplicate the anabolic effects of the seeds. We found that the 96% ecdysteroid increased the mass of the developing quails in a dose-dependent manner, with the rate of increase proportional to the ecdysteroid content in the seeds; there was a 115% increase in living mass with 100 mg kg^–1 of pure 20E compared with 109.5% increase with 100–180 mg kg^–1 20E equivalents in the seeds. We conclude that the plethora of growth-promoting, vitamin-like effects induced in vertebrates byLeuzea is mediated by ecdysteroids.     

The relationship of intraglandular colloid production to hormone synthesis

Summary The production of intraglandular colloid, brought about by the cyclic breakdown of intermediate lobe cells, is related to the synthesis of hormones in the hypophysis. By analyzing the shift of the amino acid, cystine, during various phases of the gland's cycle it is apparent that hormones, as well as other protein determinants of immunological importance, are transported by way of the intraglandular cleft to the venous circulation and to the cerebrospinal fluid.This study was supported by a grant from the National Research Council of Canada.     

Der Einfluss sogenannter Ovulationshemmer auf die Esteraseaktivität des Endometriums

Summary Histochemical investigations were carried out in the endometrium of guinea-pigs after administration of Anovlar (4 mg ethinylnortestosterone-acetate and 0.05 mg ethynylestradiol). Histochemically a decrease of non-specific esterase activity was found in the endometrial as well as in the glandular epithelium after Anovlar treatment. The relationship of this enzyme to synthetic steroid hormones is briefly discussed.     

Facteurs influençant la fertilité des mâles deXenopus laevis D. (Batracien anoure)

Summary Under the conditions prevailing at the Station de Zoologie expérimentale (University of Geneva), the fertility of males ofXenopus laevis decreases every year in the autumn (Figure). Long-day treatment significantly increases the fertility and leads to the conclusion that the decrease is due to photoperiodic influences. Treatment with Antex (Leo) (i.e. a follicle-ripening hormone) for 3 weeks highly activates spermatogenesis at a time when the gonads normally remain inactive.

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Remerciements: Je dois ma reconnaissance à Mlle K. Ponse, Professeur d'endocrinologie, pour ses conseils et les discussions sur l'effet des différentes hormones gonadotropes; au Professeur A. Linder, Professeur de statistique mathématique, qui a bien voulu faire l'analyse statistique des croisements; et à mes collègues Mme F. Vanderhaeghe, Dr ès sc., et Mlle A. Droin, Dr ès sc., pour leurs observations et discussions. Le travail technique a été effectué avec l'appui du Fonds National Suisse pour la Recherche Scientifique N 2551.     

Prevention of estrogenic inhibition of adrenal 686-1686-1686-1686-2686-2686-2in rats

Summary The urinary protein _2u stimulates adrenal ⁵-3 dehydrogenase activity and prevents adrenal enlargement in estrogen-treated adult male rats.Acknowledgements. Dehydroepiandrosterone used in this study was donated by Organon(India) Ltd, Calcutta. This work received financial support from University Grants' Commission, New Delhi. The author's thanks are due to Prof. A. K. Maiti and Prof. C. Deb, Department of Physiology, Calcutta University, for their constant encouragement.     

Differential expression and dosage compensation of theα-amylase gene inDrosphila miranda

Summary The-amylase gene ofDrosophila miranda is located on the X²-and on the neo-Y-chromosome, both developing sex chromosomes. Crosses between strains carrying different electrophoretically distinguishable alleles of the-amylase gene were performed. Females of the F₁ offspring showed the expected heterozygosity, while the males proved to be hemizygous for this locus. Only the gene on the X²-chromosome is expressed, whereas the corresponding gene on the neo-Y-chromosome is not. Estimates of the-amylase activity in crude homogenates of male and female flies suggest strongly that the-amylase gene is dosage compensated inD. miranda. In contrast to this situation, in all otherDrosophila species the-amylase allele is autosomal and hence not dosage compensated.Acknowledgments. We would like to thank Betty C. Moore, for the kind supply ofD. miranda strains. For the help and advice in the electrophoretic separation of the-amylase variants we are indebted to Dr W. Pinsker. This work was supported by a grant from the Fonds zur Förderung der wissenschaftlichen Forschung, P5413 (Austria).     

Arginine-vasopressin,lysine-vasopressin,and oxytocin,C14-labeled in the glycine residue

Zusammenfassung Die Synthese von Arginin-Vasopressin, Lysin-Vasopressin und Oxytocin, deren Glycinrest eine¹⁴C-Markierung trägt, wird mit Hilfe der Festkörpermethode nachMerrifield beschrieben.

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Supported by National Institutes of Health grants No. AM-13567 and No. AM-10080 and the Atomic Energy Commission.

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Abbreviations follow the rules of the IUPAC-IUB Commission on Biochemical Nomenclature in Biochemistry5, 2485 (1966). All optically-active amino acids are ofl-configuration. The following additional abbreviations were used: N-hydroxysuccinimide ester (OSu), ethanol (EtOH), methanol (MeOH), acetic acid (AcOH),n-butanol (n-BuOH), pyridine (Pyr) and N,N-dicyclohexylcarbodiimide (DCCI). Protected peptides and hormones were visualized on thinlayer plates according to the procedure byH. Zahn andE. Rexroth, Z. analyt. Chem.148, 181 (1955). The biological activities of the hormones were measured against the U.S.P. Posterior Pituitary Reference Standard; the four-point design was used for these bioassays and standard errors were calculated according to the method ofC. I. Bliss,The Statistics of Bioassay (Academic Press, New York, N.Y. 1952).

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Acknowledgments. The authors wish to thank Mr.D. Schlesinger for some of the amino acid derivatives used, and MissM. Wahrenburg and Mrs.A. Silverman for bioassays.     

Antigénicité et pouvoir immunogène des toxines extraites des venins d'Elapidae et d'Hydrophiidae

Summary In this article the results are reported of recent experiments concerning the antigenicity and the immunogenic properties of some basic toxic proteins recently extracted from snake venoms. A serological classification of these substances is proposed. 3 groups have now been determined. As most of the low molecular weight proteins (<10.000) the immunogenicity of the toxin ofNaja nigricollis, taken as an example, is poor. The influence of polymerization of this toxin, and the adjuvant effect of the Freund mixture on the production of specific antibodies, are described. By affinity chromatography, using Sepharose 4B as a carrier, antibodies against this toxin were separated from the other proteins of the antiNaja nigricollis horse immune-serum. They belong to the IgT immunoglobulins. By the same technique, when erabutoxin a fromLaticauda semifasciata is covalently linked to the Sepharose, antibodies reacting with both this toxin and the toxin were separated from the same immuneserum. This confirms that an immunological relationship exists between the toxin of an Elapidae:Naja nigricollis, and the erabutoxin a of an HydrophiidaeLaticauda semifasciata.     

The distribution of some enzymes involved in the steroidogenesis of hen's ovary

Riassunto È stata studiata con metodi istochimici la distribuzione della ⁵-3-idrossisteroide deidrogenasi ( ⁵-3-HSDH) e delle 17-idrossisteroide deidrogenasi (17-HSDH), DPN- e TPN-dipendenti, nell'ovario di gallina ovulante. Mentre la ⁵-3-HSDH è presente in tutti i tessuti a secrezione steroide dell'ovario, la 17-HSDH è localizzata solo nelle cellule della granulosa.     

Zur Umsetzung von 3α-Hydroxy-5β-Steroiden mit Blei(IV)-acetat

Summary On treatment of 3-hydroxy-5-steroids with lead tetra-acetate formation of 3, 9-oxides is observed. The yields of this ring closure reaction decrease significantly in the order 11-keto, ^{9, 11}-ene and ring-C saturated compounds.     

Über die Ausscheidung von 3β-Hydroxy-17-Ketosteroiden im Harn von Meerschweinchen

Summary 11-hydroxy-epiandrosterone was isolated and identified from urine of normal untreated female guinea pigs. After cold and hot acid hydrolysis of the urine, we found another 3-hydroxy-17-oxosteroid. Its character was investigated by several methods and we suppose this steroid is9(11)-epiandrosterone, an artificial product of 11-hydroxy-epiandrosterone.     

Effect of genome size andrrn gene copy numbers of PCR amplification products of 16S rRNA genes from mixed bacterial species

Results and conclusion As determined by image analysis of SYBR green-stained amplification products the experimentally determined ratio corresponded well with the expected ratio calculated from the number ofrrn genes per equimolar amount of DNA in mixtures containing DNA ofEscherichia coli and Thermus thermophilus and DNA ofPseudomonas aeruginosa and T. thermophilus. The values for the pairBacillus subtilis and T. thermophilus showed higher deviation from the predicted value. The dependence of the amount of 16S rDNA amplification products on these two parameters makes it impossible to quantify the number of species present in 16S rDNA clone library of an environmental sample, as long as these two parameters are unknown for these species.     

“The True” in Gottlob Frege's “Über die Grundlagen der Geometrie”

In this essay, I examine the metaphysical and metalogical ramifications of Gottlob Frege's controversy with David Hilbert and Alwin Korselt, over Hilbert's Grundlagen der Geometrie. These ramifications include(1) Korselt's original appeals to general metatheoretic Deutungen (interpretations);(2) Hilbert's puzzling belief that whatever is consistent in some sense exists; and(3) Frege's semantic monist conviction that theoretical sense and reference (mathematical and other) must be eindeutig lösbar (uniquely solvable).My principal conclusions are(4) that Frege's position in (3) represented a pervasively dogmatic presumption that his newly discovered quantification theory must have a propositional metatheory (the True; the False); and(5) that this needless assumption adversely affected not only his polemic against the moderate semantic relativism of Hilbert and Korselt, but also his reception of type-theoretic ideas, and greatly facilitated his vulnerability to the sort of self-referential inconsistency Russell discovered in Grundgesetz V.These conclusions also seem to me to provide a conceptual framework for several of Frege's other arguments and reactions which might seem more particular and disparate. These include(6) his arbitrary restrictions on the range of second-order quantification, which undercut his own tentative attempts to give accounts of independence and semantic consequence;(7) his uncharacteristic hesitation, even dismay, at the prospect that such accounts might eventuate in a genuinely quantificational metamathematics, whose Gegenstände (objects) might themselves be Gedanken (thoughts); and, perhaps most revealingly(8) his otherwise quite enigmatic, quasi-stoic doctrine that genuine formal deduction must be from premises that are true.A deep reluctance to pluralize or iterate the transition from theory to meta-theory would also be consonant, of course, with Frege's vigorous insistence that there can be only one level each of linguistic Begriffe (concepts) and Gegenstände (objects). With hindsight, such an assumption may seem more gratuitous in the philosophy of language (where it contributed, I would argue, to Wittgenstein's famous transition to the mystical in 6.45 and 6.522 of the Tractatus); but its more implausible implications in this wider context seemed to emerge more slowly.In the mathematical test-case discussed here, however, such strains were immediately and painfully apparent; the first models of hyperbolic geometry were described some thirty years before Frege drafted his polemic against Hilbert's pioneering exposition. It is my hope that a careful study of Frege's lines of argument in this relatively straightforward mathematical controversy may suggest other, parallel approaches to the richer and more ambiguous problems of his philosophy of language.Niemand kann zwei Herren dienen. Man kann nicht der Wahrheit dienen und der Unwahrheit. Wenn die euklidische Geometrie wahr ist, so ist die nichteuklidische Geometrie falsch, und wenn die nichteuklidische wahr ist, so ist die euklidische Geometrie falsch.No one can serve two masters. One cannot serve truth and untruth. If Euclidean geometry is true, non-Euclidean geometry is false, and if non-Euclidean [geometry] is true, Euclidean geometry is false. Über Euklidische Geometrie [Frege 1969], p. 183.     

Cytogénétique desLeggada: (1) La formule chromosomique deMus (Leggada)bufo Th., (2) Nouvelles données sur la délétion portant sur le bras court d'unX chezMus (Leggada)triton Th

Summary The author treats 2 topics connected with his studies on the cytogenetics of the African pigmy-mice. (1)Mus (Leggada) bufo Th. shows the primitive complement already detected in other species or subspecies (minutoides ssp ₁,indutus, tenellus, setulosus): 2N=36,N.F.=36, sex chromosomesPR. (2) The deletion of the short arm of oneX-chromosome (X _dc ) was previously observed as heterozygous mutation by 4 in a sample of 7 and 5 . A more important sample (18 , 21 ) gives the following results: 11 X-X, 10 X-X _dc , 18 X-Y. The occurrence of X _dc -X _dc and of X _dc -Y is also very improbable. It is not easy to understand how the chromosomeX _dc may persist in the population if the complementsX _dc -X _dc andX _dc -Y are lethal, which seems to result from these observations.     

Hydrolysis of amino acid β-naphthylamides by aminopeptidases in the parotid gland

Zusammenfassung Die Aktivität der Aminopeptidasen in Ohrspeicheldrüsen wurde gemessen. Glycyl-Prolin-naphthylamid, Alanin-naphthylamid, Leucin-naphthylamid, Methionin-naphthylamid, und Arginin-naphthylamid wurden von der Mikrosomenfraktion und der löslichen Fraktion schnell gespalten. Das Glycyl-Prolin-naphthylamid spaltende Enzym war in Ohrspeicheldrüsen in relativ grösserer Menge vorhanden. Die Aufspaltung von Glycyl-Prolin-naphthylamid in Glycyl-Prolin und-Naphthylamin wurde papierchromatographisch nachgewiesen.     

Programmierte Molekeln

Summary Polypeptides and proteins are compared with programmed machines capable of automatic functioning and of regulation. Among the regulatory processes, endocrine regulation is examined in more detail. Parallels are drawn to kybernetic devices, and concepts of organization and read out of information contained in polypeptide hormones are briefly dealt with. These views lead to recent work on a fluorescent derivative of ACTH, dansyllysine-21-ACTH-(1–24)-tetrakosipeptide, which is capable of binding to potential receptors. By means of fluorescence polarization it was discovered that this hormone derivative is specifically and strongly bound to glucose-6-phosphate dehydrogenase from cow adrenals.Other work is described which pertains to the question of whether it is possible to write an original program in polypeptide language in order to obtain molecules with new (biological) activities. We were able to construct a bicyclic peptide, S, S-bis-cycloglycyl-hemicystyl-glycyl-glycyl-prolyl, capable of specifically complexing potassium cations and transporting them through a lipophilic membrane. It is hoped to be able to achieve coupling of this transport to redox energy differences.

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11. Paul-Karrer-Vorlesung in der Aula der Universität Zürich am 12. November 1969.