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PubMed1983

Androstenedione-mediated inhibition of 11 beta-hydroxylation in monolayer cell cultures of fetal calf adrenals.

The possibility that the formation of androstenedione by fetal calf adrenal cells in culture is linked to their decreased ability to form cortisol and corticosterone was investigated. Fetal calf adrenal cells metabolise radioactive adrostenedione to two major products which coelute on thin layer chromatography with 11 beta-hydroxyandrostenedione and 11 beta-hydroxytestosterone. When the cells are incubated with 11-deoxycortisol or 11-deoxycorticosterone in the presence of androstenedione there is a dose dependant inhibition of cortisol and corticosterone formation. Further studies with progesterone showed an accumulation of 11-deoxycortisol and 11-deoxycorticosterone in cells incubated simultaneously with androstenedione. The results demonstrate that exogenous androstenedione can have dramatic effects on steroidogenesis in the fetal calf adrenal and suggest that the accumulation of androstenedione in the medium of cultured andrenocortical cells is responsible, at least in part, for the decreased formation of cortisol and corticosterone.

Adrenal Glands↗

PubMed1983

Characterization of the increased estrogen synthesis in skin fibroblasts from the Sebright bantam.

We have utilized the Sebright bantam chicken as a model system to explore the regulation of estrogen formation in peripheral tissues. As the result of a gene mutation, Sebright males develop a female feathering pattern associated with an increase in estrogen synthesis in skin and in fibroblasts cultured from skin. To provide insight into the mechanisms by which estrogen synthesis is increased we examined several parameters of the aromatase reaction in homogenates from control ovaries, Sebright ovaries and fibroblasts grown from Sebright skin: the pH optima; the apparent Km's for testosterone, 19-nortestosterone, androstenedione, 16-hydroxyandrostenedione, and NADPH; the apparent Ki's for 4-hydroxyandrostenedione, aminoglutethimide, dehydroepiandrosterone, and 19-hydroxytestosterone; and the inactivation of the reaction by heating. No qualitative differences were identified in the enzyme from Sebright and control birds.

Androstenedione↗

PubMed1984

Microbial transformation of testosterone by Aspergillus fumigatus.

Microbial transformation has been employed for the preparation of the potentially important 15 beta-hydroxytestosterone which was obtained by fermentation of testosterone with a typical strain of Aspergillus fumigatus. The metabolite was characterized by employing 1H and 13C NMR, mass spectrometry and i.r. analysis. High performance liquid chromatography (HPLC) was used to examine the purity of the product and formation of other minor metabolites.

Aspergillus fumigatus↗

PubMed1985

Metabolism of testosterone by human semen.

Following the incubation of human sperm and seminal plasma with 13C2-labelled testosterone, the main metabolite, identified by gas chromatography-mass spectrometry (GC-MS), was 4-androstene-3,17-dione. In addition, 6 alpha- and 6 beta-hydroxytestosterone were identified. The more common metabolites of testosterone were not detected, and it is possible that the high substrate-tissue ratio influenced the result. Incubation of individual sperm and seminal plasma specimens with [14C]testosterone resulted in the identification, by specific activity measurements, of 4-androstene-3,17-dione in almost every specimen but with a widely varying conversion rate. Dihydrotestosterone, which on general grounds was considered a likely metabolite, could not be positively confirmed as such, although in some samples its presence was suspected. Gas chromatography-mass spectrometry was also used to identify steroids in sperm and seminal plasma extracts. Some, but not all the steroids identified as present in such extracts by other investigators, were found. During the course of this work C18 Sep-Pak cartridges were successfully used to prepare fractions suitable for SP-Sephadex and TEAP-Lipidex chromatography and subsequent analysis by GC-MS. Their use eliminated the need for purification steps otherwise necessary.

Androstenedione↗

PubMed1987

Influence of a prolonged tamoxifen administration on steroidogenesis by incubated rat testes.

Tamoxifen was administered i.m. for 9 days to adult male rats in a daily dose of 100 micrograms or 1 mg. The treatment resulted in a significant reduction of the plasma levels of testosterone and LH, without modification of the plasma levels of FSH and of the testes weight. Upon incubation, the testes from the tamoxifen-treated rats produced less testosterone and 7 alpha-hydroxytestosterone, but metabolized [4-14C]testosterone in the same way as the control animals. Small doses of hCG (0.5 i.u. for 9 days) were unable to modify the tamoxifen effect on the testicular function, while tamoxifen significantly inhibited the increase of the plasma levels of testosterone induced by the administration of moderate doses of hCG (1.5 i.u. or 2.5 i.u. for 9 days) to hypophysectomized rats. Tamoxifen treatment, however, did not modify significantly the reactivity of the testes towards high doses of hCG (10 i.u.), administered either 2 h before sacrifice or for 9 days. It is concluded that a prolonged administration of tamoxifen in the rat has, besides an indirect effect resulting from a decrease of the LH levels, a direct inhibitory influence on the testicular testosterone formation, which can be reversed by high doses of hCG.

Androgens↗

PubMed1975

Post-ejaculatory vocalization in castrated rats treated with various steroids.

Five groups of rats were observed for sexual behavior as intact subjects and in the 3 weeks following castration. Particular emphasis was placed upon ultrasonic vocalization recorded during the refractory period (RP) following ejaculation. All rats received daily injections (100 mug test steroid + 100 mug dihydrotestosterone propionate, DHTP) from the day of castration. Treatment groups were: Testosterone propionate (TP) + DHTP, N = 5; 19-hydroxytestosterone propionate (19HTP) + DHTP, N = 6; Oestradiol dipropionate (OP) + DHTP, N = 5; DHTP (200 mug/day), N = 6; Vehicle only, N = 7. Ejaculation and normal RPs were maintained with TP, 19HTP and OP treatments. In rats treated with DHTP alone or vehicle only ejaculatory ability declined and RPs increased in length. Ultrasonic vocalization was normal in all rats except those treated with OP, where it was either reduced or absent. In Week 4 treatments in TP + DHTP and OP + DHTP groups were reversed. During Weeks 5-7 vocalization was gradually restored in rats that previously received OP and partially inhibited in animals previously treated with TP. These results indicate that; (1) vocalization may not be dependent on the presence of testicular androgens and, (2) OP has a gradual inhibitory effect on vocalization when given at high doses and this effect is reversible.

Animals↗

PubMed1976

Synthesis of new steroid haptens for radioimmunoassay. Part I. 15beta-Carboxyethylmercaptotestosterone-bovine serum albumin conjugate. Measurement of testosterone in male plasma without chromatography.

A radioimmunoassay (RIA) procedure has been developed for measurement of testosterone in male plasma after ether:chloroform (4:1) extraction of the plasma sample without resorting to chromatography. The highly specific anti-testosterone serum was generated from both rabbits and sheep immunized with 15beta-carboxyethylmercapto-testosterone-BSA conjugate. The synthesis of 15beta-carboxyethylmercaptotestosterone and the preparation of its BSA conjugate are described. The high affinity (Ka=2.38 X 10(9) liters/mole) antiserum binds 50% of 50 picograms of tritiated testosterone at working dilutions of 1:100,000 to 1:200,000. Both 5alpha and 5beta-dihydrotestosterone compounds exhibited less than 2% cross-reaction. The only other steroids that showed minor cross-reaction were 11beta-hydroxytestosterone (3.8%), progesterone (2.1%), corticosterone (1.6%), and deoxycorticosterone (7.7%).

Antibody Specificity↗

PubMed1978

Properties of the aromatase system associated with the mitochondrial fraction of human placenta.

The aromatase system associated with the mitochondrial fraction of human term placenta, present at 35--50% the specific activity of the microsomal enzyme, is substantially the same as the microsomal enzyme as determined by the following: 1) The rate of aromatization of androstenedione, 19-nortestosterone, and 16alpha-hydroxytestosterone in mitochondria was a nearly constant proportion of the microsomal rate; 2) Sensitivity to carbon monoxide was the same; 3) The magnitude of cytochrome P-450 Type I spectral interactions with androgen substrates was a constant proportion in mitochondria and microsomes; 4) Sensitivity to an antibody raised against hepatic microsomal NADPH-cytochrome c reductase was the same. When inner and outer mitochondrial membrane subfractions were prepared, the predominant aromatase activity was associated with the outer membrane preparation. This aromatase activity could not be accounted for by microsomal contamination as determined by inosine diphosphatase activity, a microsomal marker. After correction, the rate of aromatization in the outer membrane preparation was almost six times that in the inner membranes and three times that of the whole mitochondrial fraction.

Androstenedione↗

PubMed1980

Kinetic study of HCG induced decrease of microsomal 7 alpha-hydroxylase activity in rat testes.

Microsomes from rat testes were incubated with varying concentrations of 14C labelled testosterone and androstenedione. The production of 7 alpha-hydroxytestosterone and 7 alpha-hydroxyandrostenedione was followed; Km and Vm values were calculated from Lineweaver-Burk curves. A sustained treatment of rats with HCG resulted in a considerable decrease of the maximal 7 alpha-hydroxylation rats (Vm) whereas the Km value was not changed. Vm 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 7 alpha-hydroxylation capacity of testicular microsomes is at least in part due to non-competitive inhibition of the enzyme.

Androstenedione↗

PubMedDate not supplied

Measurement of five androgens in the blood of immature and maturing male rainbow trout, Salmo gairdneri (Richardson).

Antisera for radioimmunoassay (RIA) against testosterone, 11-oxo-testosterone, 11 beta-hydroxytestosterone, 11-oxo-androstenedione, and 11 beta-hydroxyandrostenedione were raised in female rabbits. The RIAs were tested for their suitability for quantification of the steroids after thin layer chromatography of ether extracts from plasma pools of immature and maturing male rainbow trout. Results from control experiments of the RIAs (buffer blanks, sensitivity, cross reactivity, intra- and inter-assay coefficients of variation, accuracy) were all within a normal range. These RIAs should be helpful tools to test the significance of the hypothesis concerning the "interrenal-liver-gonad axis" which has been proposed to account for the high androgen levels in male trout during high reproductive activity.

Androgens↗

PubMed1990

The use of stable isotopes and gas chromatography/mass spectrometry in the identification of steroid metabolites in the equine.

Stable isotope gas chromatography/mass spectrometry has been used successfully in the elucidation of structures of urinary steroid metabolites in the horse and in the identification of metabolites isolated from in vivo perfusion and in vitro incubation studies using equine tissue preparations. Deuterium-labeled steroids, testosterone, dehydroepiandrosterone, and 5-androstene-3 beta,17 beta-diol have been synthesized by base-catalyzed isotope exchange methods and the products characterized by gas chromatography/mass spectrometry. [16,16(-2)H2]Dehydroepiandrosterone (plus radiolabeled dehydroepiandrosterone) was perfused into a testicular artery of a pony stallion and was shown to be metabolized into 2H2-labeled testosterone, 4-androstenedione, isomers of 5-androstene-3,17-diol, 19-hydroxytestosterone, and 19-hydroxy-4-androstenedione. In further studies, equine testicular minces have been incubated with 2H2-labeled and radiolabeled dehydroepiandrosterone and 5-androstene-3 beta, 17 beta-diol. The metabolites, whose identity was confirmed by stable isotope gas chromatography/mass spectrometry, proved the interconversion of the two substrates, as well as formation of testosterone and 4-androstenedione. The aromatization of dehydroepiandrosterone was also confirmed, together with the formation of an isomer of 5(10)-estrene-3,17-diol from both substrates showing 19-demethylation without concomitant aromatization. In studies of the feto-placental unit, the allantochorion was shown to aromatize [2H5]testosterone to [2H4]estradiol, the loss of one 2H from the substrate being consistent with aromatization of the A ring. The formation of 6-hydroxyestradiol was also confirmed in this study. The same technique has been valuable in determining the structure of two metabolites of nandrolone isolated from horse urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Allantois↗

PubMed1992

A sensitive enzyme-linked immunosorbent assay (ELISA) for testosterone: use of a novel heterologous hapten conjugated to penicillinase.

A microplate enzyme-linked immunosorbent assay (ELISA) has been developed for the measurement of testosterone in plasma. The assay uses a heterologous system consisting of a novel hapten 4-(17 beta-hydroxy-3-oxoestra-4,9-dien-11 beta-yl)butanoic acid (1) conjugated to penicillinase (beta-lactamase). The key reaction in the synthesis of the hapten was the cuprate-mediated 1,4-conjugate addition on 3,3,17,17-bis-ethylenedioxy-5 alpha,10 alpha-oxido-estr-9(11)-ene by the Grignard reagent derived from trimethyl 4-bromoorthobutyrate; this regiospecifically introduces the 11 beta-butanoate function. The hapten-penicillinase conjugate was used in the assay in conjunction with the immunoglobulin G (IgG) fraction derived from a previously characterized, highly specific, antitestosterone serum raised against a testosterone-19-O-carboxymethyl ether-bovine serum albumin (T-19-O-CME-BSA) conjugate. This unique system represents one incorporating three elements of structural heterology: bridge, site, and ring heterology between the antigen hapten and enzyme-linked hapten. The limit of detection was 10 pg of testosterone with a sensitivity range between 15 and 1,000 pg. A low level of cross-reactivity with 5 alpha-dihydrotestosterone (6.17%) and 11 beta-hydroxytestosterone (1.03%) was noted. No interference was noted with other common androgens, estradiol, or progesterone. The sensitivity and selectivity observed in the assay may be attributable to the selection of penicillinase as the enzyme marker and the elements of conformational heterology between the antigen-linked and enzyme-conjugated steroid haptens.

Enzyme-Linked Immunosorbent Assay↗

PubMed1991

Modulation of rat hepatic microsomal monooxygenase enzymes and cytotoxicity by diallyl sulfide.

Diallyl sulfide (DAS) and other organosulfur compounds inhibit chemically induced carcinogenic and toxic responses in rodent model systems. A possible mechanism of action is the inhibition of the hepatic cytochrome P450IIE1-dependent bioactivation of the procarcinogens and protoxicants. Previous work showed competitive inhibition by DAS of N-nitrosodimethylamine (NDMA) demethylase activity in vitro, and a reduction in the microsomal level of P450IIE1 after in vivo treatment with DAS. The present studies demonstrated a time- and dose-dependent decrease of hepatic microsomal P450IIE1 activity, induction of P450IIB1 and pentoxyresorufin dealkylase activity, and moderate induction of ethoxyresorufin dealkylase activity by oral DAS treatment. DAS treatment elevated P450IIB1 mRNA but had no effect on P450IIE1 mRNA. Treatment with putative metabolites of DAS, diallyl sulfoxide and diallyl sulfone, led to similar modulations in monooxygenase activities, but the decrease of P450IIE1 activity by the sulfone occurred more rapidly. In studies in vitro, diallyl sulfone caused a metabolism-dependent inactivation of P450IIE1, but such inactivation was not observed with DAS or diallyl sulfoxide. The profile of microsomal testosterone metabolism after DAS treatment indicated an enhancement of P450IIB1-dependent 16 beta-hydroxylase activity, and a decrease in 6 beta-hydroxytestosterone production possibly related to a lower level of P450IIIA1 or IIIA2. When rats were subjected to a 48-hr fast and DAS treatment, the starvation-induced microsomal P450IIE1 level was decreased by DAS. Inhibition of hepatotoxicity due to exposure to P450IIE1 substrates, CCl4 and NDMA, by DAS was observed under a variety of treatment schedules.

Allyl Compounds↗

PubMed1996

Engineering of a sugar-derivatized porous network for hepatocyte culture.

Many tissue engineering applications require a scaffold or template conducive to cell attachment and maintenance of functions. It may also be advantageous in some cases for these scaffolds to have a controlled porous architecture to facilitate cellular or tissue ingrowth. In this study, we have engineered a porous carbohydrate-derivatized substrate for hepatocyte culture. Polystyrene foams, with pore sizes up to 100 microns, fabricated by phase separation from a homogeneous naphthalene solution, were derivatized with lactose and heparin, both of which are known to promote rat hepatocyte attachment and maintenance of its differentiated functions. Rat hepatocytes cultured on these derivatized foams exhibited a rounded cellular morphology with many microvilli evident on the surface of the cells. The hepatocytes showed an increase in albumin secretion for the first 3 days of culture in a defined, serum-free medium, and dropped back to initial levels by the end of 7 days. The production of cytochrome P450-dependent hydroxytestosterone metabolites were also measured. Two testosterone metabolites were maintained and five others were present but decreased over a culture period of 1 week. These carbohydrate-derivatized porous substrates may be useful for large-scale culture of hepatocytes, toxicology screening and for use in a liver assist device.

Animals↗

PubMed1990

Purification and characterization of 3-ketosteroid-delta 1-dehydrogenase from Nocardia corallina.

The inducible 3-ketosteroid-delta 1-dehydrogenase of Nocardia corallina which catalyzes the introduction of a double bond into the position of carbon 1 and 2 of ring A of 3-ketosteroid has been obtained in four steps with a 50% yield and 360-fold purification. The enzyme is homogeneous as judged by SDS-gel electrophoresis and is a monomeric protein with a molecular weight of 60,500. The isoelectric point of the enzyme is about 3.1. The enzyme contains 1 mol of flavin adenine dinucleotide per mol of protein, and has a typical flavoprotein absorption spectrum with maxima of 458, 362 and 268 nm. The enzyme is very stable in the absence of added cofactors, and catalyzes the dehydrogenation of delta 4-3-ketosteroids in the presence of phenazine methosulfate, which acts as an excellent electron acceptor. Potassium ferricyanide and cytochrome c did not act as electron acceptors. The delta 1-dehydrogenation was also stimulated by molecular oxygen with stoichiometric production of hydrogen peroxide and delta 1,4-3-ketosteroid. The optimum pH is 10 for dehydrogenation using phenazine methosulfate, and is between 8.5 and 10 for the oxidase reaction. The enzyme oxidizes a wide variety of 3-ketosteroids, but not 3 beta-hydroxysteroids. 3-Ketosteroids having an 11 alpha- or 11 beta-hydroxyl group were oxidized at slow rates. The purified enzyme catalyzes efficiently aromatization of the A-ring of 19-nortestosterone and 19-norandrostenedione to produce estradiol and estrone. 19-Hydroxytestosterone, 19-hydroxyandrostenedion and 19-oxotestosterone were converted to the respective phenolic steroids with cleavage of the C10 side-chain. Activities of 3-ketosteroid-delta 4-dehydrogenase, delta 5-3-ketosteroid-4,5-isomerase, 3 beta-hydroxysteroid dehydrogenase and 17 beta-hydroxysteroid dehydrogenase were not observed in the purified preparations. Properties of this novel flavoprotein enzyme are discussed.

Amino Acids↗

PubMed1987

Gonadotropin stimulated androgen secretion of rainbow trout (Salmo gairdneri Richardson) testis in vitro.

1. The secretion of five androgens was quantified from trout testes under GTH-stimulation in vitro before and after the onset of milt production, and a general increase of basal and GTH stimulated androgen secretion was recorded during this period. 2. 11-Ketotestosterone, testosterone, and in spermiating males, 11 beta-hydroxytestosterone as well showed GTH dependent concentration increases, while androstenetrione and 11 beta-hydroxyandrostendione were found in highly variable amounts. 3. 17 beta-Hydroxyandrogen glucuronides in the medium (with the exception of testosterone) and tissue androgens were by far exceeded by the free androgens in the medium.

Androgens↗

PubMed1981

Control of estrogen synthesis in the testis of the infant rat by FSH and androgen.

The experiments studied the ability of androgens to stimulate in vivo the production of estradiol by the testes of the 12-day-old rat as well as interactions between FSH and androgens in this regard. The content of testosterone and estradiol in the testes was measured by RIA of methanolic extracts which were purified on columns of Sephadex LH-20. It was found that androstenedione, testosterone and 19-hydroxytestosterone were able to stimulate estradiol formation in the testes; the response was optimal 3 h after s.c. injection. The stimulatory effect was absent after injection of 5 alpha-reduced androgens. It was concluded that the ability of a single injection of androgen to increase the content of estradiol in the testes was due to provision of additional substrate for aromatization by the Sertoli and/or Leydig cells. Priming of rats for 2 days with testosterone (60 microgram/g bw daily) resulted in a reduction of concentration of LH and FSH in plasma and was associated with an inhibition of the estradiol response to a subsequent injection of testosterone. If priming with testosterone was followed by an injection of FSH, more estradiol was formed than when the FSH injection was preceded by an oil or dihydrotestosterone priming regimen. It was concluded that the inhibition of testosterone-induced aromatization noted after testosterone priming was due to low gonadotropin secretion rather than a direct effect on the testis and that priming of the infant rat with androgen enhanced the response to FSH because such treatment provided additional substrate for aromatization.

Androgens↗

PubMed1991

Equine testicular aromatase: substrates specificity and kinetic characteristics.

1. In the stallion, estrogens were synthesized and sulfated in vivo by the testis. 2. The equine testicular enzyme aromatized androgens and 19-norandrogens with similar velocity, but not 16 alpha-hydroxytestosterone or epitestosterone in contrast to the human placental aromatase. 3. One single enzyme was implicated in the aromatization of androstenedione, testosterone, 19-norandrostenedione and 19-nortestosterone by ETMES. 4. During the process of androstenedione aromatization by ETMES, 19-hydroxyandrostenedione and 19-oxoandrostenedione were released and 4-hydroxyandrostenedione was a competitive inhibitor causing an additional irreversible enzyme inactivation which is what occurs with HPMES. 5. Dihydrotestosterone was a potent competitive inhibitor of aromatase activity.

Androgens↗