- A kinetic analysis of the 5α-reductases from human prostate and liver
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A kinetic analysis of the 5α-reductases from human liver and prostate is presented. Human prostatic 5α-reductase follows an ordered sequential mechanism in which NADPh binds first followed by testosterone. The order of release of products is DHT followed by NADP+. The apparent K(m) of prostatic 5α-reductase for testosterone is 0.0339 ± 0.006μM, while the apparent K(m) for NADPh is 2.52 ± 0.65μM. Human liver 5α-reductase also follows a sequential mechanism. The apparent K(m) of the liver enzyme is 0.110 ± 0.08μM; the apparent K(m) for NADPH is 6.2 ± 0.6μM. The fact that both the liver and prostatic 5α-reductases have a sequential kinetic mechanism rules out the possibility that the reduction of testosterone to dihydrotestosterone involves an electron transport system as previously proposed.
- Houston,Chisholm,Habib
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- Comparative study of human steroid 5α-reductase isoforms in prostate and female breast skin tissues: Sensitivity to inhibition by finasteride and epristeride
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Steroid 5α-reductase (5-AR) catalyses the reduction of testosterone (T) to dihydrotestosterone (DHT). The 5α-reductase found in human benign prostatic hyperplasia (BPH) has been compared with that found in human breast skin tissue in respect of sensitivity to inhibition by Finasteride and Epristeride. Kinetic studies showed the presence of two isoforms of 5α-reductase in benign prostatic hyperplasia indicated by low and high Km isoforms for testosterone, while female breast skin tissue contained only one isoform. The isoforms differ in their affinity for the inhibitors Finasteride and Epristeride, both compounds being more effective for the low Km 5α-reductase isoform than the high Km 5α-reductase of prostatic tissue, with Finasteride displaying competitive inhibition and Epristeride uncompetitive. Finasteride and Epristeride are also inhibitors of skin 5α-reductase, which possesses a comparable Ki for Finasteride to that of the low Km prostatic enzyme, but Epristeride was a less potent inhibitor of the skin enzyme relative to the prostate isoform. These results suggest that the inhibitors have therapeutic potential, other than for treatment of benign prostatic hyperplasia, for treating skin disorders influenced by the action of dihydrotestosterone and warrant further investigation.
- Ranjan, Mala,Diffley, Penny,Stephen, Gita,Price, David,Walton, Terence J.,Newton, Russell P.
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- Stereochemistry of Reduction by the 5α-Reductase Enzyme of Penicillium decumbens and the 1H NMR Assignment of 5α-Dihydrotestosterone
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Reduction of the alkenic bond of testosterone and androst-4-ene-3,7-dione by the 5α-reductase enzyme of Penicillium decumbens with trans stereochemistry.
- Holland, Herbert L.,Xu, Weili,Hughes, Donald W.
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- Significance of the delta 5 and delta 4 steroidogenic pathways in the hamster preovulatory follicle.
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Isolated hamster granulosa cells and theca from preovulatory follicles were incubated in vitro for 2 and 6 h in the absence/or presence of LH and steroid substrates. The purpose of the experiments was to determine, in theca, the relative activities of the delta 5 and delta 4 pathways under controlled conditions, and to compare the ability of granulosa cells and theca to form progesterone from exogenous pregnenolone. The results of the experiments show that the delta 5 pathway in theca predominates before and up to 2 h after LH stimulation. The delayed effect of LH after 2 h is a switch from delta 5 to delta 4 as the major metabolic pathway. Progesterone formation from exogenous pregnenolone is 7 to 10 times greater in unstimulated granulosa cells than in theca. Acute effects of LH lead to increased conversion of exogenous pregnenolone to progesterone in granulosa cells but not theca. LH does, however, acutely stimulate the thecal conversion of DHEA to androstenedione. The longer term effect of LH in both cell types is to increase pregnenolone conversion to progesterone.
- Makris,Olsen,Ryan
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- Spatial Localization and Quantitation of Androgens in Mouse Testis by Mass Spectrometry Imaging
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Androgens are essential for male development and reproductive function. They are transported to their site of action as blood-borne endocrine hormones but can also be produced within tissues to act in intracrine and paracrine fashions. Because of this, circulating concentrations may not accurately reflect the androgenic influence within specific tissue microenvironments. Mass spectrometry imaging permits regional analysis of small molecular species directly from tissue surfaces. However, due to poor ionization and localized ion suppression, steroid hormones are difficult to detect. Here, derivatization with Girard T reagent was used to charge-tag testosterone and 5α-dihydrotestosterone allowing direct detection of these steroids in mouse testes, in both basal and maximally stimulated states, and in rat prostate. Limits of detection were ~0.1 pg for testosterone. Exemplary detection of endogenous steroids was achieved by matrix-assisted laser desorption ionization and either Fourier transform ion cyclotron resonance detection (at 150 μm spatial resolution) or quadrupole-time-of-flight detection (at 50 μm spatial resolution). Structural confirmation was achieved by collision induced fragmentation following liquid extraction surface analysis and electrospray ionization. This application broadens the scope for derivatization strategies on tissue surfaces to elucidate local endocrine signaling in health and disease.
- Cobice, Diego F.,Livingstone, Dawn E. W.,MacKay, C. Logan,Goodwin, Richard J. A.,Smith, Lee B.,Walker, Brian R.,Andrew, Ruth
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- Synthetic method of androstenone
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The invention relates to the field of medicine preparation, in particular to a synthetic method of androstenone. The preparation method comprises the following steps: S100, catalyzing testosterone by a catalyst, and carrying out hydrogenation addition reaction to obtain a compound I; S200, converting a 17-site hydroxyl group of the compound I into a halogen group or a sulfonate group which is easy to leave, so as to obtain a compound II; and S300, subjecting the compound II and alkali to an elimination reaction under the heating condition, namely, a dehalogenation reaction or a desulphonate reaction, so as to obtain androstenone. The synthesis method of androsteneone has the following beneficial effects: the raw materials are cheap and easy to obtain; the process is simple, the route is short, and the requirement on equipment is low; dangerous reagents and operation are avoided, and large-scale industrial production is easy to realize; and isomer impurities are not generated in the synthesis process, and the yield of the target product androsteneone is high.
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Paragraph 0087-0089; 0097-0099; 0102-0104; 0107-0109
(2021/05/12)
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- Formation of 5α-dihydrotestosterone from 5α-androstane-3α,17β-diol in prostate cancer LAPC-4 cells – Identifying inhibitors of non-classical pathways producing the most potent androgen
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5α-Dihydrotestosterone (5α-DHT) possesses a great affinity for the androgen receptor (AR), and its binding to AR promotes the proliferation of prostate cancer (PC) cells in androgen-dependent PC. Primarily synthesized from testosterone (T) in testis, 5α-DHT could also be produced from 5α-androstane-3α,17β-diol (3α-diol), an almost inactive androgen, following non-classical pathways. We reported the chemical synthesis of non-commercially available [4-14C]-3α-diol from [4-14C]-T, and the development of a biological assay to identify inhibitors of the 5α-DHT formation from radiolabeled 3α-diol in LAPC-4 cell PC model. We measured the inhibitory potency of 5α-androstane derivatives against the formation of 5α-DHT, and inhibition curves were obtained for the most potent compounds (IC50 = 1.2–14.1 μM). The most potent inhibitor 25 (IC50 = 1.2 μM) possesses a 4-(4-CF3-3-CH3O-benzyl)piperazinyl methyl side chain at C3β and 17β-OH/17α-C[tbnd]CH functionalities at C17 of a 5α-androstane core.
- Boutin, Sophie,Roy, Jenny,Maltais, René,Poirier, Donald
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supporting information
(2019/11/26)
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- The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1
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Testosterone and its 5α-reduced form, 5α-dihydrotestosterone, were previously thought to represent the only active androgens in humans. However, recent studies have shown that the potent androgen, 11-ketotestosterone, derived from the adrenal androgen precursor, 11β-hydroxyandrostenedione, may in fact serve as the primary androgen in healthy women. Yet, despite recent renewed interest in these steroids, their downstream metabolism has remained undetermined. We therefore set out to investigate the metabolism of 11-ketotestosterone by characterising the 5α- or 5β-reduction commitment step. We show that inactivation of 11-ketotestosterone is predominantly driven by AKR1D1, which efficiently catalyses the 5β-reduction of 11-ketotestosterone, committing it to a metabolic pathway that terminates in 11-ketoetiocholanolone. We demonstrate that 5α-reduction of 11-ketotestosterone is catalysed by SRD5A2, but not SRD5A1, and terminates in 11-ketoandrosterone, but is only responsible for a minority of 11-ketotestosterone inactivation. However, as 11-ketoetiocholanolone is also generated by the metabolism of the glucocorticoid cortisone, 11-ketoandrosterone should be considered a more specific urinary marker of 11-ketotestosterone production.
- Barnard, Lise,Nikolaou, Nikolaos,Louw, Carla,Schiffer, Lina,Gibson, Hylton,Gilligan, Lorna C.,Gangitano, Elena,Snoep, Jacky,Arlt, Wiebke,Tomlinson, Jeremy W.,Storbeck, Karl-Heinz
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- Mild Deprotection of Dithioacetals by TMSCl/NaI Association in CH3CN
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A mild process using a combination of TMSCl and NaI in acetonitrile is used to regenerate carbonyl compounds from a variety of dithiane and dithiolane derivatives. This easy to handle and inexpensive protocol is also efficient to deprotect oxygenated and mixed acetals as 1,3-dioxanes, 1,3-dioxolanes and 1,3-oxathianes quantitatively. As a possible extension of this method, it was also shown that nitrogenated substrates such as hydrazones, N-tosylhydrazones, and ketimines reacted well under these conditions to give the expected ketones in high yields. The methodology proposed herein is a good alternative to the existing methods since it does not use metals, oxidants, reducing agents, acidic or basic media, and keto-products were obtained in high to excellent yields.
- Yao, Yunxin,Zhao, Guangkuan,Hamze, Abdallah,Alami, Mouad,Provot, Olivier
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p. 5775 - 5779
(2020/08/17)
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- Purified mCPBA, a Useful Reagent for the Oxidation of Aldehydes
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Purified mCPBA is a useful reagent for the oxidation of several classes of aldehyde. Although linear unbranched aliphatic aldehydes are oxidized to the corresponding carboxylic acids, α-branched ones undergo Baeyer–Villiger oxidation to formates. α-Branched α,β-unsaturated aldehydes provide enolformates and/or epoxides, which can be saponified to α-hydroxy ketones with shortening of the carbon chain by 1 carbon. Unbranched α,β-unsaturated aldehydes undergo an interesting Baeyer–Villiger oxidation/epoxidation/formate migration/BV oxidation cascade, which results in formyl-protected hydrates with an overall loss of two carbon atoms.
- Horn, Alexander,Kazmaier, Uli
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p. 2531 - 2536
(2018/03/21)
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- A preparation method of male nandrolone (by machine translation)
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A male nandrolone preparation method, namely in order to 4 - androstenedione (abbreviated as 4AD) as raw materials, the first 4AD with the original carboxylic acid triethyl in organic solvent, acid catalyzed reaction shall be etherification 3 - ethoxy - androstane - 3, 5 - diene - 17 - one; then the etherification in the organic solvent, adding metal borohydride reducing agent, etherification molecule in the 17 bit keto also restored to hydroxy, shall also the original 3 - ethoxy - androstane - 3, 5 - diene - 17 - ol; then also the original in the organic solvent, adding hydrogenation reaction catalyst, selective hydrogenation also the original molecule of 5 bit double bond, shall be hydride 3 - ethoxy - androstane - 3 - en - 17 - ol; finally the hydride in an organic solvent, acid catalytic hydrolysis extraction male nandrolone; the method of the invention compared with the traditional production method, raw material sources are wide, short synthetic route, process convenient and environmental protection, high product yield, economy and environmental protection, the production cost is reduced 35 - 40%, which is very beneficial to industrial production. (by machine translation)
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- Characterization of hamster NAD+-dependent 3(17)β-hydroxysteroid dehydrogenase belonging to the aldo-keto reductase 1C subfamily
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The cDNAs for morphine 6-dehydrogenase (AKR1C34) and its homologous aldo-keto reductase (AKR1C35) were cloned from golden hamster liver, and their enzymatic properties and tissue distribution were compared. AKR1C34 and AKR1C35 similarly oxidized various xenobiotic alicyclic alcohols using NAD+, but differed in their substrate specificity for hydroxysteroids and inhibitor sensitivity. While AKR1C34 showed 3α/17β/20α-hydroxysteroid dehydrogenase activities, AKR1C35 efficiently oxidized various 3β- and 17β-hydroxysteroids, including biologically active 3β-hydroxy-5α/β-dihydro-C19/C21-steroids, dehydroepiandrosterone and 17β-estradiol. AKR1C35 also differed from AKR1C34 in its high sensitivity to flavonoids, which inhibited competitively with respect to 17β-estradiol (Ki 0.11-0.69 μM). The mRNA for AKR1C35 was expressed liver-specific in male hamsters and ubiquitously in female hamsters, whereas the expression of the mRNA for AKR1C34 displayed opposite sexual dimorphism. Because AKR1C35 is the first 3(17)β-hydroxysteroid dehydrogenase in the AKR superfamily, we also investigated the molecular determinants for the 3β-hydroxysteroid dehydrogenase activity by replacement of Val54 and Cys310 in AKR1C35 with the corresponding residues in AKR1C34, Ala and Phe, respectively. The mutation of Val54Ala, but not Cys310Phe, significantly impaired this activity, suggesting that Val54 plays a critical role in recognition of the steroidal substrate.
- Endo, Satoshi,Noda, Misato,Ikari, Akira,Tatematsu, Kenjiro,El-Kabbani, Ossama,Hara, Akira,Kitade, Yukio,Matsunaga, Toshiyuki
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p. 425 - 434
(2015/11/27)
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- Rabbit 3-hydroxyhexobarbital dehydrogenase is a NADPH-preferring reductase with broad substrate specificity for ketosteroids, prostaglandin D2, and other endogenous and xenobiotic carbonyl compounds
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3-Hydroxyhexobarbital dehydrogenase (3HBD) catalyzes NAD(P) +-linked oxidation of 3-hydroxyhexobarbital into 3-oxohexobarbital. The enzyme has been thought to act as a dehydrogenase for xenobiotic alcohols and some hydroxysteroids, but its physiological function remains unknown. We have purified rabbit 3HBD, isolated its cDNA, and examined its specificity for coenzymes and substrates, reaction directionality and tissue distribution. 3HBD is a member (AKR1C29) of the aldo-keto reductase (AKR) superfamily, and exhibited high preference for NADP(H) over NAD(H) at a physiological pH of 7.4. In the NADPH-linked reduction, 3HBD showed broad substrate specificity for a variety of quinones, ketones and aldehydes, including 3-, 17- and 20-ketosteroids and prostaglandin D2, which were converted to 3α-, 17β- and 20α-hydroxysteroids and 9α,11β- prostaglandin F2, respectively. Especially, α-diketones (such as isatin and diacetyl) and lipid peroxidation-derived aldehydes (such as 4-oxo- and 4-hydroxy-2-nonenals) were excellent substrates showing low Km values (0.1-5.9 μM). In 3HBD-overexpressed cells, 3-oxohexobarbital and 5β-androstan-3α-ol-17-one were metabolized into 3-hydroxyhexobarbital and 5β-androstane-3α,17β-diol, respectively, but the reverse reactions did not proceed. The overexpression of the enzyme in the cells decreased the cytotoxicity of 4-oxo-2-nonenal. The mRNA for 3HBD was ubiquitously expressed in rabbit tissues. The results suggest that 3HBD is an NADPH-preferring reductase, and plays roles in the metabolisms of steroids, prostaglandin D2, carbohydrates and xenobiotics, as well as a defense system, protecting against reactive carbonyl compounds.
- Endo, Satoshi,Matsunaga, Toshiyuki,Matsumoto, Atsuko,Arai, Yuki,Ohno, Satoshi,El-Kabbani, Ossama,Tajima, Kazuo,Bunai, Yasuo,Yamano, Shigeru,Hara, Akira,Kitade, Yukio
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p. 1366 - 1375
(2013/11/19)
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- Bile acid-based 1,2,4-trioxanes: Synthesis and antimalarial assessment(1)
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A new series of bile acid-based trioxanes 23a-d, 24a-d, 25a-d, 26a, 26b, and 26d have been synthesized and assessed for their antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice by oral route. The antimalarial activity of these trioxanes showed a strong dependence on the side-chain length; shortening side-chain length lead to increase in activity. The antimalarial activity also showed even stronger dependence on the stereochemistry at C3 and C6 (C21 in Figure 5) of the trioxane moiety. Of the two diastereomers isolated of each of the trioxanes, more polar one was significantly more active than the less polar one. The more polar diastereomer of the trioxanes 26a, 26b, and 26d, were the most active compounds of the series. All these three trioxanes provided 100% protection at 24 mg/kg × 4 days. In this model β-arteether provided 100% and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively.
- Singh, Chandan,Hassam, Mohammad,Verma, Ved Prakash,Singh, Ajit Shanker,Naikade, Niraj Krishna,Puri, Sunil K.,Maulik, Prakas R.,Kant, Ruchir
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p. 10662 - 10673
(2013/02/23)
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- A new simple and high-yield synthesis of 5α-dihydrotestosterone (DHT), a potent androgen receptor agonist
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We have devised an efficient procedure for the synthesis of 5α-dihydrotestosterone (DHT) (1) starting from 3β-hydroxy-5α- androstan-17-one, providing the product in unprecedented 82% yield. A reported method of using toxic Jones reagent is replaced by milder oxidizing agent (NMO/TPAP) in the synthesis of a key intermediate 17β-[(tert- butyldimethylsilyl)oxy]-5α-androstan-3-one (18). This new procedure is simple, does not require special apparatus/precautions or chromatographic purification in most of the steps.
- Purushottamachar, Puranik,Njar, Vincent C.O.
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p. 1530 - 1534
(2013/01/15)
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- Steroidal isomers with uniform mass spectra of their per-TMS derivatives: Synthesis of 17-hydroxyandrostan-3-ones, androst-1-, and -4-ene-3,17-diols
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In human sports doping control analysis most of the steroids are analyzed after enzymatic hydrolysis of the glucuronides as per-trimethylsilyl (TMS) derivatives applying gas chromatography-mass spectrometry (GC-MS). According to the recommendations of the World Anti-Doping Agency the identification of analytes should be based on retention time and on mass spectrometric characterization. This study shows that the bis-TMS derivatives of 16 specific C19 steroids, namely the stereoisomers of 5ξ-androst-1-ene-3ξ,17ξ-diol (8 isomers), androst-4-ene-3ξ,17ξ-diol (4 isomers), and 17ξ-hydroxy-5ξ-androstan-3-one (4 isomers), reveal very similar mass spectra. As a rule, when taking the retention times, which are provided as Kovac indices for all these isomers, into account, a restriction to two or three possible isomers is possible. Reliable identification should additionally include a comparison of the retention times of the analytes with the reference compounds measured concomitantly. In some cases standard addition may be appropriate. Due to the limited availability, the above mentioned isomers were synthesized by reduction of the corresponding α,β-unsaturated oxo steroids either with K-Selectride or by catalytic hydrogenation (Pd/C as catalyst). The products of the reactions were identified by means of nuclear magnetic resonance (NMR) characterization and by further reduction to the corresponding 5ξ-androstane-3ξ,17ξ-diols and GC-MS comparison with commercially available reference standards.
- Parr, Maria K.,Zapp, Josef,Becker, Michael,Opfermann, Georg,Bartz, Ulrike,Schaenzer, Wilhelm
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p. 545 - 551
(2008/02/02)
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- Passflow syntheses using functionalized monolithic polymer/glass composites in flow-through microreactors
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A chemist's wish finally becomes reality: microreactors for every synthetic laboratory! By precipitation polymerization various polymers are introduced into the irregular pore system of a porous glass rod. By embedding these rods into a housing, followed by functionalization and immobilization of reagents onto the polymer phase, versatile microreactors are obtained. With this apparatus, chemical transformations in solution can be performed, for example, a steroid derivatization (see picture).
- Kirschning, Andreas,Altwicker, Carsten,Drger, Gerald,Harders, Jan,Hoffmann, Nora,Hoffmann, Ulrich,Schnfeld, Hagen,Solodenko, Wladimir,Kunz, Ulrich
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p. 3995 - 3998
(2007/10/03)
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- Steroid transformations with Exophiala jeanselmei var. lecanii-corni and Ceratocystis paradoxa
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The fungi Exophiala jeanselmei var. lecanii-corni [IMI (International Mycological Institute) 312989, UAMH (University of Alberta Microfungus Collection and Herbarium) 8783] and Ceratocystis paradoxa (IMI 374529, UAMH 8784) have been examined for their potential in steroid biotransformation. The study has determined that E. jeanselmei var. lecanii-corni effected overall anti-Markovnikov hydration on dehydroisoandrosterone, and side-chain degradation on a variety of pregnanes. Both ascomycetes were found to carry out redox reactions of alcohols and ketones as well as 1,4 reduction of α,β-unsaturated carbonyl systems.
- Porter, Roy B.R.,Gallimore, Winklet A.,Reese, Paul B.
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p. 770 - 779
(2007/10/03)
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- Formation of 5α steroids by biotranformation involving the 5 α-reductase activity of Penicillium decumbens
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The biotransformation of a series of Δ4-3-ketosteroids by the Penicillium decumbens ATCC 10436 has been investigated. Conversion to the 5α-dihydrosteroid was observed substrates of the androsterone and pregne series: the reaction is tolerant of non-polar substituents (Cl and CH3) at C-4 of the substrate, but does not occur in the presence of a 4-hydroxyl group, or with additional unsaturation at the Δ1 or Δ6 positions. A-nor, B-nor, 3-deoxy-, and 3,5-cycloandrostanes are not reduced, but 6-methylenestestosterone is converted to a 6-methylene-5α-dihydro derivative. Several biotransformations are reported which involve oxidoreductase activity at C-3 and/or C-17, either concomitant or independent of Δ4 reduction: the substrate specificity of the oxidoreductase processes has been examined and defined by the use of 3α-hydroxy, 3β-hydroxy, 3-keto, 17β-keto substituted steroids. In this way, the existence in P. decumbens of 3β-hydroxy-3-keto and 17β-hydroxy-17-keto oxidoreductases has been demonstrated.
- Holland, Herbert L.,Dore, Sophia,Xu, Weili,Brown, Frances M.
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p. 642 - 647
(2007/10/02)
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- THE BIOTRANSFORMATION OF SOME STEROIDS BY CEPHALOSPORIUM APHIDICOLA
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Hydroxylation of 5α-androstane-3-one and 3,6-dione by C. aphidicla takes place at C-17β and, in the case of the latter, at C-5α.The fungus reduces 5α-androstan-17-one and the 3,17-dione to the 17β-alcohols. Key Word Index - Cephalosporium aphidicola; fungus; microbiological hydroxylation; steroids.
- Hanson, James R.,Nasir, Habib
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p. 831 - 834
(2007/10/02)
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- Diiodosilane. 4. Direct reduction of ketals and acetals in the presence of unprotected carbonyls. A case of inverted chemoselectivity
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Ketals and acetals are selectively reduced by diiodosilane to iodoalkanes in preference to ketones and aldehydes. This inversion of the normal order of reactivity of the 'protected' and 'unprotected' carbonyls allows partial reduction of polycarbonyl compounds with unusual regio- and chemoselectivity. Thus, 8,8-(ethylenedioxy)octan-2-one, 7,7-(ethylenedioxy)octanal, 3,3-(ethylenedioxy)-androstan-17-one and 3,3-(ethylenedioxy)pregnane-11,20-dione are converted to the corresponding iodo compounds.
- Keinan,Sahai,Shvily
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p. 641 - 643
(2007/10/02)
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- Electrocatalytic Hydrogenation Using Precious Metal Microparticles in Redox-Active Polymer Films
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Glassy carbon felt electrodes have been modified by electrodeposition of poly(pyrrole-viologen) films (derived from N,N'-dialkyl-4,4'-bipyridinium salts), followed by electroprecipitation of precious metal (Pt, Pd, Rh, or Ru) microparticles.The resulting electrodes have been proved to be active for the electrocatalytic hydrogenation of conjugated enones (2-cyclohexen-1-one, cryptone, carvone, isophorone), styrene, and benzonitrile in aqueous media (pH 1).Despite low loading of metal catalysts, high electric and product yields and a long term stability of these cathodes have been observed.The influence of the metal loading and the polymer structure on the catalytic efficiency as well as the selectivity obtained according to the metal catalyst used have been studied.Comparision with results previously reported for other catalytic cathodes like Pt/Pt, Pd/C, or Raney nickel electrodes proves the high efficiency of these microparticles within redox polymer film based electrodes.
- Coche, Liliane,Ehui, Bernadette,Limosin, Daniele,Moutet, Jean-Claude
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p. 5905 - 5910
(2007/10/02)
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- The Reduction of Steroid 2α-Fluoro 4-En-3-ones
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Reduction of testosterone with potassium tri-(R,S)-sec-butylborohydride gives predominantly the allylic 3β-alcohol, while 2α-fluorotestosterone is converted solely to 2α-fluoro-4-androstene-3α,17β-diol, and 2α-fluoro-4-androstene-3,17-dione to 2α-fluoro-3α-hydroxy-4-androsten-17-one.Reduction of testosterone with (R,R)- or (S,S)-Rh-DIOP and dihydrosilanes give predominantly allylic alcohols, while with the same catalysts and monohydrosilanes no allylic alcohols are found, the 4-double bond being instead reduced.The chirality of the DIOP reagents contributes only to a minor extent to stereoselectivity of 3-ketone reduction.
- Goeendos, Gyoergy,McGirr, Larry G.,Jablonski, Chester R.,Snedden, Walter,Orr, James C.
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p. 3057 - 3059
(2007/10/02)
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- The Selective Protection of the 3-Ketone Functions of Steroids as Heptafluoro-p-tolyl Enol Ethers
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Conjugated and unconjugated 3-ketone functions in steroids react with octafluorotoluene at above 100 deg C in the presence of caesium fluoride to give heptafluoro-p-tolyl enol ethers.The related but unusually reactive Wieland-Miescher ketone (11) reacted at room temperature in the presence of tetra-n-butylammonium fluoride.Enones were regenerated from their derivatives by acidic hydrolysis.Hydrolysis of the derivative (10) of 4,5α-dihydroxytestosterone was slu but sodium methoxide regenerated the parent steroid.The methods have been applied in a synthesis of deuterium-labelled testosterone.
- Jarman, Michael,McCague, Raymond
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p. 1129 - 1134
(2007/10/02)
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- STUDIES ON THE KINETICS OF THE INTERACTION OF 7α-HYDROXYTESTOSTERONE WITH THE STEROID 5α-REDUCTASE
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Microsomal preparations from adult male rat testicular interstitial cells were incubated with tritiated testosterone.Added 7α-hydroxytestosterone, (7α,17β-dihydroxy-4-androsten-3-one), at levels which appear to exist in the adult testis, inhibited production of labelled 5α-reduced steroids in a graded fashion.This interaction is not competitive and occurs only at high substrate levels, such as those found in steroid-producing organs.Relationships to pubertal changes in steroid metabolism are discussed.
- Mittler, James C.
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p. 135 - 142
(2007/10/02)
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- STUDY OF THE DIRECT EFFECT OF LHRH AGONIST ON TESTICULAR 17-HYDROXYLASE AND 5α-REDUCTASE ACTIVITIES IN NON-HYPOPHYSECTOMIZED ADULT RATS TREATED WITH AN ANTI-LUTEINIZING HORMONE SERUM
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In order to study both direct and pituitary-mediated mechanisms of action of the LHRH analogue 6, des-Gly-NH210>LHRH ethylamide upon testicular steroidogenesis in adult rat, we compared the effects of the agonist when administered alone or concomitantly with an anti-LH serum to non-hypophysectomized rats.Testicular steroid contents and in vitro progesterone and testosterone metabolism were determined.Anti-LH serum administration was able to prevent 5α-reductase stimulation by the agonistic peptide, but not the inhibition of 17-hydroxylase activity.These data suggest that modulation of 17-hydroxylase involves both direct and pituitary-mediated processes, while 5α-reductase stimulation is mainly if not only due to a pituitary-mediated mechanism.
- Carmichael, Rejean,Belanger, Alain
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- Mild and Effective Removal of Dithioketal Protecting Groups by Triarylamine Cation Radicals as Homogeneous Electron Transfer Agents
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1,3-Dithianes 2 can effectively be converted into the parent carbonyl compounds 7 by a very mild oxidative procedure using tri-p-tolylammoniumyl (1a+.) or tris(4-bromophenyl)ammoniumyl (1b+.) as homogeneous electron transfer agents.The yields are equally good for the cleavage by stoichiometric amounts of the triarylammoniumyl hexachloroantimonates as well as for the indirect electrochemical procedure using catalytic amounts of the triarylamine together with electrochemical generation and regeneration of the cation radicals.In the case of 1,3-dithiolanes 3 the application of stoichiometric amounts of tris(4-bromophenyl)ammoniumyl hexa chloroantimonate is very effective while during the indirect electrochemical procedure the deposition of polymeric sulfur compounds onto the electrode surface has to be prevented by the use of a flowthrough cell.In all cases the conditions for the cleavage are so mild that hydroxy functions and double bonds are tolerated without problems.
- Platen, Martin,Steckhan, Eberhard
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p. 1679 - 1694
(2007/10/02)
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- REMOVAL OF METOXYETHOXYMETHYL ETHERS WITH TRIMETHYLSILYL CHLORIDE-SODIUM IODIDE
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Trimethylsilyl chloride-sodium iodide has been used for the mild removal of methoxyethoxymethyl ethers.
- Rigby, James H.,Wilson, JoAnn Zbur
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p. 1429 - 1432
(2007/10/02)
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- Stereochemistry of the Palladium-catalyzed Hydrogenation of 3-Oxo-4-ene Steroids. V. A Kinetic Study in Basic and Acidic Media
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Effects of the β-methyl group at C-10 and some oxygen functions (=O, OH, OAc) at C-11, C-17, and C-20 on the rates of hydrogenation of 3-oxo-4-ene steroids have been studied with palladium catalyst in pyridine or THF/HBr as solvent.In contrast to the hydrogenation in pyridine, the rate in THF/HBr was greatly depressed by the presence of 10β-methyl group.The reactivity of the steroids was enhanced by the oxygen functions, in particular, by 11, 17-dioxo group.The effects of the substituents are discussed from a mechanistic consideration based on the obtained results.
- Nishimura, Shigeo,Momma, Yasuhiro,Kawamura, Hideo,Shiota, Michio
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p. 780 - 783
(2007/10/02)
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- Radical-induced Reduction of α,β-Unsaturated Steroid Ketones with Tributyltin Hydride
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Conjugated steroid ketones are reduced stereoselectively with tributyltin hydride in the presence of azobisisobutyronitrile as radical initiator to give the corresponding saturated ketones in high yields.
- Laurent, Henry,Esperling, Peter,Baude, Guenter
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p. 1996 - 1999
(2007/10/02)
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- Preparation of a Polymer-supported Diol and Its Use in isolating Aldehydes and Ketones from Mixtures and as a Protecting Group for Aldehydes and Ketones
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Reaction of cross-linked chloromethylated polystyrenes with 3-mercaptopropane-1,2-diol and sodium hydroxide under phase-transfer conditions gave polymers containing diol residues.A range of aldehydes and ketones were successfully bound to these polymers via acetal formation.The aldehydes and ketones were released by treating the products with aqueous dioxane in the presence of toluene-p-sulphonic acid.The polymer-supported diol could be used to isolate aldehydes or ketones from mixtures with other compounds and to separate a 3-oxosteroid from a 17- or a 20- oxosteroid.The supported diol was successfully used to protect the aldehyde group of undec-10-enal whilst the terminal vinyl group was transformed into -CH2CH2OCOPh.Attempts to monoprotect dicarbonyl compounds were unsuccessful.
- Hodge, Philip,Waterhouse, Janette
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p. 2319 - 2323
(2007/10/02)
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- Comparative studies of androgen metabolism in theca and granulosa cells of human follicles in vitro
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In eight separate experiments, theca and granulosa were isolated from human follicles (5-25 mm in diameter) , and their capacities to metabolize radiolabelled testosterone in 24 hour cultures were assessed. Theca metabolized testosterone primarily to androstenedione, however significant aromatization to estradiol-17β and to estrone was also observed. Granulosa metabolized testosterone primarily to estradiol-17β and estrone, while smaller quantities were converted to androstenedione. In seven of these experiments, the intermediate of aromatization, 19-hydroxytestosterone, was identified. In six of these experiments, theca, when compared to granulosa, produced more androstenedione but less estradiol-17β and estrone. 5α-Reduced androgens were non-detectable or produced in small quantities. In a single experiment, metabolism of androstenedione was compared to metabolism of testosterone by both theca and granulosa. Theca metabolized androstenedione to testosterone in smaller quantities than testosterone to androstenedione. Granulosa metabolized androstenedione to testosterone in higher quantities than testosterone to androstenedione. Both theca and granulosa aromatized androstenedione more readily than testosterone.
- Moon,Duleba
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p. 419 - 430
(2007/10/02)
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- OXIDATION OF ALCOHOLS BY ELECTROCHEMICALLY REGENERATED NICKEL OXIDE HYDROXIDE. SELECTIVE OXIDATION OF HYDROXYSTEROIDS
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Primary alcohols, α,ω-diols and secondary alcohols are easily transformed into carboxylic acids, dicarboxylic acids or ketones, respectively, by heterogeneous oxidation with nickel oxide hydroxide electrochemically regenerated at a nickel hydroxyde electrode.The results are discussed in comparison to those of the nickel peroxide and chromic acid oxidation.The oxidation rate decreases with increasing steric hindrance of the alcohol, thus allowing the selective oxidation of the 3-position in hydroxysteroids.
- Kaulen, Johannes,Schaefer, Hans-J.
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p. 3299 - 3308
(2007/10/02)
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- Estradiol-17β inhibition of androgen uptake, metabolism and binding in epididymis of adult male rats in vivo: A comparison with cyproterone acetate
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The effects of estradiol-17β on androgen uptake, metabolism and binding were studied in rat epididymis in vivo in comparison with cyproterone acetate. Steroids (250 ug/100 g body weight) were injected 5 min prior to 3H-testosterone in castrate rats. Estradiol-17 β inhibited 3H-testosterone uptake into epididymal cytosol by 58% as compared to 38% by cyproterone acetate. 3H-Testosterone uptake into epididymal nuclei was inhibited 95% by estradiol-17 β and 83% by cyproterone acetate. Total bound radioactivity in cytosol fractions was reduced to a greater extent by estradiol-17 β than cyproterone acetate when either 3H-testosterone or 3H-dihydrotestosterone was injected. Binding of 3H-dihydrotestosterone to nuclear receptors was completely abolished by estradiol-17 β ; whereas approximately 20% binding remained in the nuclear extract after cyproterone acetate treatment. Metabolism of 3H-testosterone in vivo was also altered by estradiol-17 β, resulting in diminished conversion to 3H-dihydrotestosterone. Cyproterone acetate, on the other hand, did not affect 3H-testosterone metabolism. Estradiol-17 β and cyproterone acetate inhibited in vitro binding of 3H-dihydrotestosterone to the intracellular cytoplasmic receptor, but not the intraluminal androgen binding protein (ABP). These data suggest that estradiol-17 β may have a more potent antiandrogenic effect on the epididymis than cyproterone acetate due to inhibition of 5 α reduction of testosterone as well as binding to the androgen receptor.
- Tindall,French,Nayfeh
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p. 257 - 268
(2007/10/02)
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- Male contraceptive steroids and methods of use
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The steroids of the present invention have been found to be useful as male contraceptives when administered orally. Upon cessation of administration of the male contraceptive steroids of the present invention the male promptly regains normal fertility.
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- ANDROGEN METABOLISM IN MALE AND FEMALE BREAST TISSUE
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Incubation studies have been carried out using normal breast tissue and breast tissue from patients with gynecomastia, mammary dysplasia and breast carcinoma to determine the pattern of androstenedione metabolism.All tissues formed estrone (E1) and testosterone (T) in all incubations.Estradiol (E2) was isolated in incubations of tissue from 1 of 6 patients with mammary dysplasia, 5 of 6 patients with gynecomastia and in all incubations with normal and carcinoma tissue.Estrone formation was lowest in mammary dysplasia and gynecomastia, and higher in apparently normal breast tissue.The greatest E1 formation was found in incubations with breast carcinoma tissue, although there was considerable variation within this tissue group.Estradiol formation was low in all tissues, with the highest conversion rates in carcinoma tissue.Testosterone formation in carcinoma tissue was greater than in mammary dysplasia or gynecomastia, but similar to apparently normal tissue.These results indicate that breast tissue from different pathological states varies in its capacity to aromatize androstenedione (A) to estrogenic products and to convert it to other androgens.They have also shown that the pattern of metabolism is distinctive for the nature of the pathological abnormality.
- Perel, E.,Davis, S.,Killinger, D. W.
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p. 345 - 352
(2007/10/02)
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- An analysis of the metabolites of progesterone produced by isolated Sertoli cells at the onset of gametogenesis
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Sertoli cells isolated from 7 day old rats were maintained in culture and incubated with [14C]-progesterone for 20 h. The cells and media were extracted with ether/chloroform and the extracts chromatographed two-dimensionally on TLC and the radioactive metabolites visualized by autoradiography. Nine of the metabolites (constituting about 88% of total metabolite radioactivity) were identified by relative mobilities of the compounds and their derivatives in TLC and GC systems and by recrystallizations with authentic steroids as the following: 20α-hydroxypregn-4-en-3-one, 3α-hydroxy-5α-pregnan-20-one, 5α-pregnane-3α,20α-diol, 17β-hydroxy-5α-androstan-3-one, 5α-pregnane-3,20-dione, 17-hydroxypregn-4-ene-3,20-dione, testosterone, 5α-androstane-3α,17β-diol and androst-4-ene-3,17-dione. Over 71% of the metabolite radioactivity was due to 20α-hydroxypregn-4-en-3-one, the major metabolite. 5α-reduced pregnanes constituted about 12% and C19 steroids comprised about 2.9% of the radioactivity of the metabolites. Calculation of relative steroidogenic enzyme activities from initial reaction rates suggested the following activities in μunits/mg Sertoli cell protein: 20α-hydroxysteroid oxidoreductase (20α-HSO; 7.71), 5α-reductase (4.77), 3α-HSO (3.57), 17α-hydroxylase (0.93), 17β-HSO (0.34) and C17-C20 lyase (0.34). The relatively high rate of steroidogenic enzyme activities in the Sertoli cells of young rats may indicate that Sertoli cells are less dependent on Leydig cell steroidogenesis than has been assumed. Since nearly all the metabolites of progesterone and testosterone are now identified, it is possible to construct a picture of Sertoli cell steroidogenic activity.
- Wiebe,Tilbe,Buckingham
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p. 561 - 577
(2007/10/02)
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- CONJUGATION OF ANDROGENS AND ESTROGENS BY HUMAN BREAST TUMORS IN VITRO
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The metabolism of 3H-androstenedione (Δ4-A) and 3H-estriol (E3) was studied in 12 human breast tumors.Part of each tumor was analyzed for estrogen receptor content.Aliquots of tumor homogenates were incubated for 2 hr separately with 3H-Δ4-A and 3H-E3 in the presence of appropriate cofactors.No distinct differences emerged in the profiles of the unconjugated metabolites of 3H-Δ4-A, the major compounds in the approximate order of descendence being androsterone, androstanedione, testosterone, 5α-androstane-3α,17β-diol, epiandrosterone, and dihydrotestosterone.One tumor homogenate from an infiltrating lobular carcinoma converted 3H-Δ4-A to glucosiduronate metabolites (11percent), of which androsterone, 6.4percent; testosterone, 1.6percent; and androstanediol, 0.6percent predominated.The homogenate of this tumor and two other tumors converted 3H-E3 to 3H-E3-3S.Conversions of E3 to E3-3S in the other tumor homogenates were less than 0.6percent.No correlation between receptor content and the capability of the tumor to conjugate Δ4-A or E3 evolved.However, correlations between steroid hormone metabolism and tumor histopathology may exist.
- Raju, Uma,Blaustein, Ancel,Levitz, Mortimer
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p. 685 - 696
(2007/10/02)
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- Kinetic study of HCG induced decrease of microsomal 7α-hydroxylase activity in rat testes
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Microsomes from rat testes were incubated with varying concentrations of 14C labelled testosterone and androstenedione. The production of 7α-hydroxytestosterone and 7α-hydroxyandrostenedione was followed; K(m) and V(m) values were calculated from Lineweaver-Burk curves. A sustained treatment of rats with HCG resulted in a considerable decrease of the maximal 7α-hydroxylation rate (V(m)) whereas the K(m) value was not changed. V(m) of microsomes from normal rats, when incubated with microsomes from HCG-treated animals, was also decreased substantially. It is concluded that HCG-induced depression of 7α-hydroxylation capacity of testicular microsomes is at least in part due to non-competitive inhibition of the enzyme.
- Eechaute,Lacroix,Leusen
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p. 647 - 660
(2007/10/02)
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- PREPARATION OF α,β-UNSATURATED CARBOXYLIC ACID ESTERS BY THE REACTION OF ACI-NITROESTERS WITH ETHOXYCARBONYLMETHYLENETRIPHENYLPHOSPHORANE
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The reaction of ethoxycarbonylmethylenetriphenylphosphorane with aci-nitroesters derived from 2,6-di-t-butyl-4-nitrophenol and alcohols afforded α,β-unsaturated carboxylic esters.When mono-aci-nitroester of 1,3-butanediol or 1,6-hexanediol was used, (E)-ethyl 5-hydroxy-2-hexenoate or (E)-ethyl 8-hydroxy-2-octenoate was obtained.
- Mitsunobu, Oyo,Kimura, Junji,Shimizu, Tatsuhiko,Kawashima, Atsushi
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p. 927 - 930
(2007/10/02)
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