Metabolic control mechanisms in mammalian systems. Involvement of adenosine 3′:5′-cyclic monophosphate in androgen action

1. The ability of exogenously administered cyclic AMP (adenosine 3′:5′-monophosphate) to exert andromimetic action on certain carbohydrate-metabolizing enzymes was investigated in the rat prostate gland and seminal vesicles. 2. Cyclic AMP, when injected concurrently with theophylline, produced marked increases in hexokinase, phosphofructokinase, glyceraldehyde phosphate dehydrogenase, pyruvate kinase, and two hexose monophosphate-shunt enzymes, as well as α-glycerophosphate dehydrogenase activity in accessory sexual tissues of castrated rats. The 6-N,2′-O-dibutyryl analogue of cyclic AMP caused increases of enzyme activity that were greater than those induced by the parent compound. 3. Time-course studies demonstrated that, whereas significant increases in the activities of most enzymes occurred within 4h after the injection of cyclic AMP, maximal increases were attained at 16–24h. 4. Increase in the activity of the various prostatic and vesicular enzymes was dependent on the dose of cyclic AMP; in most instances, 2.5mg of the cyclic nucleotide/rat was sufficient to elicit a statistically significant response. 5. Administration of cyclic AMP and theophylline also produced stimulation of enzyme activities in secondary sexual tissues of immature rats. 6. Cyclic AMP and theophylline did not affect significantly any of the enzymes studied in hepatic tissue. 7. Stimulation of various carbohydrate-metabolizing enzymes in the prostate gland and seminal vesicles by cyclic AMP was independent of adrenal function. 8. Concurrent treatment with actinomycin or cycloheximide prevented the cyclic AMP- and theophylline-induced increases in enzyme activities in both castrated and adrenalectomized–castrated animals. 9. Administration of a single dose of testosterone propionate (5.0mg/100g) to castrated rats caused a significant increase in cyclic AMP concentration in both accessory sexual tissues. 10. In addition, treatment with theophylline potentiated the effects of a submaximal dose of testosterone (1.0mg/100g) on all those prostatic and seminal-vesicular enzymes that are increased by exogenous cyclic AMP. 11. The evidence indicates that cyclic AMP may be involved in triggering the known metabolic actions of androgens on secondary sexual tissues of the rat.

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A reappraisal of the effects of adenosine 3′:5′-cyclic monophosphate on the function and morphology of the rat prostate gland

Biochemical Journal ◽

10.1042/bj1340129 ◽

1973 ◽

Vol 134 (1) ◽

pp. 129-142 ◽

Cited By ~ 37

Author(s):

F. R. Mangan ◽

A. E. Pegg ◽

W. I. P. Mainwaring

Keyword(s):

Cyclic Amp ◽

Prostate Gland ◽

Hormonal Treatment ◽

Supernatant Fraction ◽

Metabolizing Enzymes ◽

Biochemical Processes ◽

Rat Prostate ◽

Glucose 6 Phosphate Dehydrogenase ◽

Stimulation Of

1. A comparison was made of the binding of 5α-dihydrotestosterone (17β-hydroxy-5α-androstan-3-one) and cyclic AMP in the rat prostate gland. Distinct binding mechanisms exist for these compounds, and cyclic AMP cannot serve as a competitor for the 5α-dihydrotestosterone-binding sites and vice versa. In contrast with the results obtained with 5α-dihydrotestosterone, very small amounts of cyclic AMP are retained in nuclear chromatin and the overall binding of this cyclic nucleotide is not markedly affected by castration. 2. Androgenic stimulation does not lead to major increases in the adenylate cyclase activities associated with any subcellular fraction of the prostate gland. Accordingly, changes in the concentration of cyclic AMP in the prostate gland after hormonal treatment are likely to be small, but these were not measured directly. 3. When administered to whole animals in vivo, small amounts of non-degraded cyclic AMP are found in the prostate gland but sufficient to promote an activation of certain carbohydrate-metabolizing enzymes in the cell supernatant fraction. The stimulatory effects of cyclic AMP were not evident with cytoplasmic enzymes engaged in polyamine synthesis or nuclear RNA polymerases. These latter enzymes were stimulated solely by the administration of testosterone. 4. By making use of antiandrogens, a distinction can be drawn between the biochemical responses attributable to the binding of 5α-dihydrotestosterone but not of cyclic AMP. Evidence is presented to suggest that the stimulation of RNA polymerase, ornithine decarboxylase and S-adenosyl-l-methionine decarboxylase is a consequence of the selective binding of 5α-dihydrotestosterone. Only the stimulation of glucose 6-phosphate dehydrogenase can be attributed to cyclic AMP or other metabolites of testosterone. 5. Overall, this study indicates that the formation of cyclic AMP is not a major feature of the androgenic response and affects only a restricted number of biochemical processes. Certainly, cyclic AMP cannot be considered as interchangeable with testosterone and its metabolites in the control of the function of the prostate gland. This difference is additionally emphasized by the failure of cyclic AMP to restore the morphology of the prostate gland in castrated animals; morphological restoration only follows the administration of androgens.

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Studies on Locust Rectum: II. Identification of Specific Ion Transport Processes Regulated by Corpora Cardiaca and Cyclic-AMP

Journal of Experimental Biology ◽

10.1242/jeb.86.1.225 ◽

1980 ◽

Vol 86 (1) ◽

pp. 225-236

Author(s):

J. H. SPRING ◽

J. E. PHILLIPS

Keyword(s):

Cyclic Amp ◽

Ion Transport ◽

Time Course ◽

Transport Processes ◽

Electrogenic Transport ◽

Corpora Cardiaca ◽

Before And After ◽

Net Flux ◽

Unidirectional Fluxes ◽

Stimulation Of

Please send reprint requests to J. E. Phillips. 1. The unidirectional fluxes of 36Cl− and 22Na+ across short-circuited locust recta bathed in a simple NaCl saline were followed with time. Unidirectional fluxes and net flux of 22Na+ to the haemocoel side all remained constant for at least 4 h and were unaffected by either corpora cardiaca homogenate (CC) or cAMP. 2. Both CC and cAMP stimulated influx and net flux of 36Cl− to the haemocoel side. Over the whole time course of the experiment, i.e. both before and after stimulation, net Cl− flux approximately equalled the shortcircuit current (ISC). 3. Neither CC nor cAMP caused substantial stimulation of ISC or transepithelial electropotential difference (PD) if all Cl− in the bathing saline was replaced by either sulphate or nitrate or acetate. 4. Acetate saline sustains ISC, PD and transepithalial resistance (R) at higher levels than does simple Cl-saline. 5. Experiments with Cl-free, SO4-salines suggest that alternate electrogenic transport processes can be slowly turned on when Cl− is absent, provided a complex saline which contains several organic constituents, or simple acetate saline, is present.

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Adrenergic control of induction of type II iodothyronine 5′-deiodinase activity in cultured mouse brown adipocytes

Biochemical Journal ◽

10.1042/bj2920303 ◽

1993 ◽

Vol 292 (1) ◽

pp. 303-308 ◽

Cited By ~ 10

Author(s):

S Pavelka ◽

J Hermanská ◽

M Baudysová ◽

J Houstĕk

Keyword(s):

Cyclic Amp ◽

Time Course ◽

Brown Fat ◽

Fat Cells ◽

Type Ii ◽

Brown Adipocytes ◽

Adrenergic Agents ◽

Adrenergic Control ◽

Stimulation Of

Iodothyronine 5′-deiodinase (5′D) of mouse brown adipocytes differentiated in cell culture was characterized in detail with respect to the adrenergic control of its biosynthesis. The stimulation of 5′D required mRNA and protein synthesis and was dependent on the stage of differentiation of the cells. The maximum induction was observed around confluence (7-day-old cells), in pre- and post-confluent cells the 5′D activity was significantly less induced. The transient responsiveness of brown fat-cells to the stimulatory effect of adrenergic agents was reflected also in the time course of the induction of 5′D by different concentrations of agonists. The maximum response occurred regularly after an 8 h incubation and implicated a rather fast turnover of the induced enzyme. On the basis of the inhibitory effects of cycloheximide and actinomycin D, the half-life of the induced 5′D and its mRNA were estimated to be 1.5 and 3.3 h respectively. The noradrenaline-induced 5′D activity was shown to be that of the type II enzyme, insensitive to propylthiouracil (PTU). The estimated values of its apparent Km for thyroxine, Km for the co-substrate dithiothreitol, and Vmax. in the presence of 1 mM PTU were 2 nM, 2.6 mM, and 0.1 pmol of I-/h per mg of protein respectively. The 5′D activity was effectively induced by forskolin and dibutyryl cyclic AMP, as well as by isoprenaline, noradrenaline and CGP-12177, but not by phenylephrine, cirazoline or oxymetazoline. This indicates that, contrary to previous observations in vivo, stimulation of 5′D in cultured brown fat-cells involves elevated cyclic AMP levels and is mediated predominantly via beta-receptors, particularly via the so-called beta 3-adrenoceptors.

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Differential effect of cis-platinum (cis-diamminedichloroplatinum) on regulation of liver and kidney haem and haemoprotein metabolism. Possible involvement of γ-glutamyl-cycle enzymes

Biochemical Journal ◽

10.1042/bj2370713 ◽

1986 ◽

Vol 237 (3) ◽

pp. 713-721 ◽

Cited By ~ 26

Author(s):

M D Maines

Keyword(s):

Enzyme Activities ◽

Time Course ◽

Parent Compound ◽

Synthetase Activity ◽

Gamma Glutamyl Transpeptidase ◽

Gamma Glutamyl ◽

Differential Effectiveness ◽

Glutamylcysteine Synthetase ◽

Ala Synthetase ◽

Cytochrome P 450

The treatment of rats with cis-platinum (cis-diamminedichloroplatinum) for 1, 3 or 7 days elicited vastly different responses in the liver and the kidney in activities of enzymes of haem-metabolism pathway and gamma-glutamyl-cycle enzymes. The differences resided in the magnitude, direction and the time course of responses. In general, the liver was by far less severely affected, and when a response was elicited, it displayed an earlier onset (1-3 days), with a return to normal at 7 days. In the kidney, however, the effects were notable after 3 days of treatment, and became more pronounced at 7 days. Specifically, the activity of 5-aminolaevulinic acid (ALA) synthetase and contents of cytochrome P-450 and the microsomal haem were decreased in the liver. In contrast, in the kidney, cytochrome P-450 and haem concentrations were significantly increased, with no change in ALA synthetase activity. The increase in the kidney haem content appeared to reflect an increased formation of haem, as suggested by the elevated activity of ferrochelatase and the concomitant decrease in tissue porphyrin levels. In the kidney, a time-dependent and pronounced inhibition of activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione production, and gamma-glutamyl transpeptidase, the first enzyme in glutathione breakdown, were observed. The enzyme activities, 7 days after treatment, were only 40 and 60% of the control values respectively. In contrast, these enzyme activities were not affected in the liver. Complexing cis-platinum with cysteine considerably intensified the entire spectrum of effects of cis-platinum in the kidney. Notably, cytochrome P-450 concentration and haem oxygenase activity were increased to about 3.5 and 6 times the control values, respectively. gamma-Glutamylcysteine synthetase activity was decreased to less than 20% of the control. It is suggested that the differential effectiveness of cis-platinum in the liver and the kidney in alternating haem metabolism is related to the vast differences which exist between these organs in the activities of gamma-glutamyl-cycle enzymes. It is further suggested that this may promote the formation in the kidney, but not in the liver, of a cis-platinum-cysteine complex that is more stable, and thus biologically more effective, than the parent compound.

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Effect of hypophysectomy on cyclic 3′,5′-nucleotide-metabolizing enzymes in the rat thyroid gland

Journal of Endocrinology ◽

10.1677/joe.0.1050363 ◽

1985 ◽

Vol 105 (3) ◽

pp. 363-369

Author(s):

A. Nagasaka ◽

H. Hidaka ◽

H. Itoh ◽

H. Nakagawa ◽

K. Kataoka ◽

...

Keyword(s):

Thyroid Gland ◽

Cyclic Amp ◽

Adenylate Cyclase ◽

Enzyme Activities ◽

Metabolizing Enzymes ◽

Cyclic Amp Phosphodiesterase ◽

Rat Thyroid ◽

Reduced Activity ◽

Autoregulatory Mechanism ◽

Rat Thyroid Gland

ABSTRACT Adenylate cyclase and cyclic AMP phosphodiesterase activities in the thyroid gland were significantly reduced after hypophysectomy, followed by a gradual restoration of the enzyme activities to the levels seen in sham-operated rats whereas a slight and persistent reduction was evident in guanylate cyclase and cyclic GMP phosphodiesterase activities in the same tissue. These changes in enzyme activities were restored by TSH administration but not by ACTH. The recovery of activity produced by TSH administration was inhibited by cycloheximide. Hypophysectomy, or TSH and cycloheximide administration, did not produce any significant changes in the concentrations of calmodulin, suggesting that the alteration of these enzyme activities is not induced by a decrease in the concentration of calmodulin. Since forskolin activation of adenylate cyclase did not restore the reduced activity in the hypophysectomized rat thyroid to the level found in the sham-operated control rat thyroid, we conclude that there is a reduction of the amount of enzyme after hypophysectomy rather than a change of the active site on adenylate cyclase. The spontaneous restoration of adenylate cyclase and cyclic AMP phosphodiesterase activities after hypophysectomy implies that cyclic AMP-metabolizing enzymes are responsive to an autoregulatory mechanism in thyroid follicular cells. J. Endocr. (1985) 105, 363–369

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EFFECTS OF MICROQUANTITIES OF TESTOSTERONE ON THE EPIDIDYMIS AND ACCESSORY GLANDS OF THE CASTRATED RHESUS MONKEY, MACACA MULATTA

Journal of Endocrinology ◽

10.1677/joe.0.0600399 ◽

1974 ◽

Vol 60 (3) ◽

pp. 399-408 ◽

Cited By ~ 13

Author(s):

N. DINAKAR ◽

RENU ARORA ◽

M. R. N. PRASAD

Keyword(s):

Rhesus Monkey ◽

Prostate Gland ◽

Seminal Vesicles ◽

Differential Threshold ◽

Ductus Deferens ◽

Intact Control ◽

Accessory Glands ◽

Male Rhesus ◽

Caput Epididymidis ◽

Stimulation Of

SUMMARY Release of testosterone from silastic implants over a period of 90 days resulted in variable stimulation of the epididymis and accessory glands of reproduction in the castrated rhesus monkey. While the weights of the seminal vesicles, prostate gland and bulbo-urethral glands were maintained at the same level as the intact control animals by four or eight implants of testosterone, those of the epididymis and ductus deferens were not affected by either dose of testosterone. Fructose in the seminal vesicles was stimulated significantly above intact control levels by eight implants of testosterone. There was no regional variation in the levels of sialic acid in the caput, corpus and cauda epididymides, but the concentrations of phospholipid and total lipid were significantly higher in the caput epididymidis. Our observations suggest there may be differential threshold requirements of androgens for the maintenance of the epididymis and accessory glands in the male rhesus monkey.

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Stimulation of glycogenolysis by adenine nucleotides in the perfused rat liver

Biochemical Journal ◽

10.1042/bj2370773 ◽

1986 ◽

Vol 237 (3) ◽

pp. 773-780 ◽

Cited By ~ 59

Author(s):

D B Buxton ◽

S M Robertson ◽

M S Olson

Keyword(s):

Cyclic Amp ◽

Adenine Nucleotides ◽

Hepatic Metabolism ◽

Hepatic Tissue ◽

Adrenergic Stimulation ◽

Portal Vein Pressure ◽

Maximal Stimulation ◽

Phenylephrine Infusion ◽

Glucose Output ◽

Stimulation Of

Infusion of adenine nucleotides and adenosine into perfused rat livers resulted in stimulation of hepatic glycogenolysis, transient increases in the effluent perfusate [3-hydroxybutyrate]/[acetoacetate] ratio, and increased portal vein pressure. In livers perfused with buffer containing 50 microM-Ca2+, transient efflux of Ca2+ was seen on stimulation of the liver with adenine nucleotides or adenosine. ADP was the most potent of the nucleotides, stimulating glucose output at concentrations as low as 0.15 microM, with half-maximal stimulation at approx. 1 microM, and ATP was slightly less potent, half-maximal stimulation requiring 4 microM-ATP. AMP and adenosine were much less effective, doses giving half-maximal stimulation being 40 and 20 microM respectively. Non-hydrolysed ATP analogues were much less effective than ATP in promoting changes in hepatic metabolism. ITP, GTP and GDP caused similar changes in hepatic metabolism to ATP, but were 10-20 times less potent than ATP. In livers perfused at low (7 microM) Ca2+, infusion of phenylephrine before ATP desensitized hepatic responses to ATP. Repeated infusions of ATP in such low-Ca2+-perfused livers caused homologous desensitization of ATP responses, and also desensitized subsequent Ca2+-dependent responses to phenylephrine. A short infusion of Ca2+ (1.25 mM) after phenylephrine infusion restored subsequent responses to ATP, indicating that, during perfusion with buffer containing 7 microM-Ca2+, ATP and phenylephrine deplete the same pool of intracellular Ca2+, which can be rapidly replenished in the presence of extracellular Ca2+. Measurement of cyclic AMP in freeze-clamped liver tissue demonstrated that adenosine (150 microM) significantly increased hepatic cyclic AMP, whereas ATP (15 microM) was without effect. It is concluded that ATP and ADP stimulate hepatic glycogenolysis via P2-purinergic receptors, through a Ca2+-dependent mechanism similar to that in alpha-adrenergic stimulation of hepatic tissue. However, adenosine stimulates glycogenolysis via P1-purinoreceptors and/or uptake into the cell, at least partially through a mechanism involving increase in cyclic AMP. Further, the hepatic response to adenine nucleotides may be significant in regulating hepatic glucose output in physiological and pathophysiological states.

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Hormonal activation of ornithine decarboxylase in embryonic chick pelvic cartilage

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1981.241.6.e454 ◽

1981 ◽

Vol 241 (6) ◽

pp. E454-E459

Author(s):

W. M. Burch ◽

H. E. Lebovitz

Keyword(s):

Cyclic Amp ◽

Ornithine Decarboxylase ◽

Time Course ◽

Embryonic Chick ◽

Metabolic Factors ◽

Rat Serum ◽

In Vitro Organ Culture ◽

Hormonal Activation ◽

Stimulation Of

We assessed whether hormones and metabolic factors known to stimulate anabolic processes in the embryonic chick pelvic cartilage would stimulate ornithine decarboxylase (ODC) activity. In vitro organ culture of these pelvic cartilages in time-course experiments with N(6)-monobutyryl cyclic AMP (BtcAMP), insulin, and 5% rat serum demonstrated maximal stimulation of ODC activity between 4 and 6 h with each factor. However, at 2 h insulin and serum significantly stimulated ODC activity (P less than 0.05) and BtcAMP did not. ODC was stimulated above control (100%) with the following factors: parathyroid hormone (PTH) (555 +/- 15%), BtcAMP (324 +/- 34%), 1-methyl-3-isobutylxanthine (MIX) (223 +/- 6%), prostaglandin E1 (PGE1) (227 +/- 15%), 3,3',5-triiodothyronine (T3) (184 +/- 22%), insulin (182 +/- 14%), multiplication-stimulating activity (MSA) (178 +/- 6%), 5% rat serum (253 +/- 57%). THe increase in ODC activity seen with BtcAMP and insulin was not due to a change in Km or a decreased rate of degradation of the enzyme. Actinomycin D (1 microgram/ml) inhibited stimulation of ODC activity by T3 and the cyclic AMP-mediated factors (PTH, BtcAMP, MIX, PGE1), but had only minimal effects on ODC stimulation by insulin, MSA, or serum. Amanitin inhibited both BtcAMP and T3 stimulation of ODC, but had no effect on insulin stimulation of ODC. Thus, hormones and metabolic factors known to stimulate anabolic processes in chick embryonic pelvic cartilage also increase ODC activity through at least two mechanisms: transcriptional (cyclic AMP-mediated and T3) and posttranscriptional (insulin, serum, MSA).

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Protein kinase activity in membrane preparations from ox brain. Stimulation of intrinsic activity by adenosine 3′:5′-cyclic monophosphate

Biochemical Journal ◽

10.1042/bj1320483 ◽

1973 ◽

Vol 132 (3) ◽

pp. 483-492 ◽

Cited By ~ 74

Author(s):

Malcolm Weller ◽

Richard Rodnight

Keyword(s):

Protein Kinase ◽

Cyclic Amp ◽

Time Course ◽

Kinase Activity ◽

Intrinsic Activity ◽

Protein Kinase Activity ◽

Ph Optimum ◽

Basal Activity ◽

Triton X ◽

Stimulation Of

1. Properties of the stimulation by cyclic AMP of the intrinsic protein kinase activity of membrane fragments from ox brain were studied. 2. Stimulation of activity declined from about 100% at 1min to less than 20% at 10min. The time-course was explained by the observation that cyclic AMP did not stimulate turnover of protein-bound serine phosphate once the membrane protein was fully phosphorylated. 3. Cyclic AMP accelerated the activity of a component of the basal activity rather than activating a different kinase. 4. The pH optimum for both the stimulated and basal activities was 7.2–7.4. NaCl (100mm) and KCl (10–100mm) inhibited the stimulated activity but did not affect the basal activity. 5. Strychnine and theophylline inhibited both activites equally, but the stimulated activity was more sensitive to inhibition by adenosine, bicuculline, vinblastin, veratrine, N-ethylmaleimide and cysteine. 6. No firm evidence for a role for endogenous cyclic AMP in the basal activity was found, but the possibility was not excluded. 7. Some 90% of both the stimulated and basal activities remained in an insoluble form after treatment of the membrane fragments with Triton X-100 (0.5%).

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INTERACTION BETWEEN PROLACTIN AND ANDROGENS IN THE ACCESSORY SEX ORGANS OF MALE MICE

Journal of Endocrinology ◽

10.1677/joe.0.0900323 ◽

1981 ◽

Vol 90 (3) ◽

pp. 323-330 ◽

Cited By ~ 12

Author(s):

E. J. KEENAN ◽

P. A. KLASE ◽

J. A. THOMAS

Keyword(s):

Dna Content ◽

Prostate Gland ◽

Seminal Vesicles ◽

Simultaneous Administration ◽

Male Mice ◽

Androgen Action ◽

Accessory Sex Organs ◽

Androgen Sensitivity ◽

Anterior Prostate ◽

Stimulation Of

Treatment of adult male mice with varying doses of prolactin increased the weights of the seminal vesicles and the anterior prostate gland. Only in the seminal vesicles were these increases in organ weights associated with increased levels of DNA. In castrated mice, prolactin alone failed to alter the weights of the accessory sex organs or DNA content. However, the simultaneous administration of prolactin and testosterone resulted in enhanced androgenic stimulation of seminal vesicle weights and their DNA content. Prostatic weights, but not DNA content, were augmented by treatment with prolactin and testosterone. Although the kidneys exhibited androgen sensitivity, prolactin failed to enhance the effect of testosterone upon the kidney. Augmentation of androgen action in the accessory sex organs was observed only after treatment with prolactin or growth hormone. Prolactin also enhanced the effects of dihydrotestosterone and 5α-androstane-3α, 17β-diol, but not of 5α-androstane-3β,17β-diol. These studies revealed that prolactin enhances the proliferative actions of androgens in mouse seminal vesicles, but not in the anterior prostate glands or the kidneys.

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