Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Daily intraperitoneal injection of cadmium chloride (0.25 or 1 mg/kg) for 21 or 45 days into rats significantly stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase, and glucose-6-phosphatase, increased the concentrations of glucose and urea in the blood, and decreased the levels of glycogen in the liver. Whereas chronic cadmium treatment failed to alter adenosine-3',5'-monophosphate phosphodiesterase (phosphodiesterase) activity, the endogenous levels of cyclic AMP (cAMP) and the activity of basal- and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased in cadmium-injected animals. Treatment with the higher dose (1.0 mg/kg) of cadmium chloride for 45 days produced greater metabolic alterations in hepatic tissue than those seen with the lower dose (0.25 mg/kg) given for a shorter period of time (21 days). Discontinuation of cadmium administration for 14 days in rats previously injected with cadmium chloride (1 mg/kg per day) for 21 days, failed to reverse the observed changes in hepatic cAMP or carbohydrate metabolism. A similar persistence of metabolic alterations was noted in rats treated with cadmium (1 mg/kg per day) for 45 days and subsequently maintained without additional treatment for 28 days. Administration of an acute dose of cadmium chloride (60 mg/kg) decreased hepatic phosphodiesterase activity and glycogen content 1 h after the injection. In addition, acute cadmium exposure increased blood glucose, serum urea, and hepatic cAMP levels, and produced an augmentation of basal- and fluoride-activated AC. However, the activities of various hepatic gluconeogenic enzymes remained unaffected in animals given an acute dose of cadmium chloride (60 mg/kg). Data provide evidence that suggests that the gluconeogenic potential of liver is markedly enhanced following chronic exposure to cadmium and that the cadmium-induced changes in carbohydrate metabolism may be associated with an enhanced synthesis of cAMP. In addition, the present study shows that the cadmium-induced metabolic alterations persist even after the cessation of cadmium treatment for a period of 28 days.
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PMID:Response of hepatic carbohydrate and cyclic AMP metabolism to cadmium treatment in rats. 16 49

1. After nicotinic acid treatment, rat liver glycogen is depleted and phosphoenolpyruvate carboxykinase activity increased, to about twice the initial value. 2. The increase in phosphoenolpyruvate carboxykinase activity promoted by nicotinic acid is prevented by cycloheximide or actinomycin D, suggesting that this effect is produced by synthesis of the enzyme de novo. 3. Despite the enhancement of phosphoenolpyruvate carboxykinase activity and glycogen depletion, which occurs 5h after the injection of nicotinic acid, the gluconeogenic capacity of liver is low and considerably less than the values found in rats starved for 48h. 4. When the livers of well-fed rats are perfused in the presence of low concentrations of glucose, the activity of phosphoenolpyruvate carboxykinase significantly increases compared with the control. 5. This increase is not related to the glycogen content, but seems to be also the result of synthesis of the enzyme de novo, since this effect is counteracted by previous treatment with cycloheximide or actinomycin D. 6. Phosphoenolpyruvate carboxykinase activity is not increased in the presence of low concentrations of circulating glucose when 40 mM-imidazole (an activator of phosphodiesterase) is added to the perfusion medium. 7. Addition of dibutyryl cyclic AMP to the perfusion medium results in an increase in phosphoenolpyruvate carboxykinase activity, in spite of the presence of normal concentrations of circulating glucose. On the other hand, the concentration of cyclic AMP in the liver increases when that of glucose in the medium is low. 8. These results suggest that, in the absence of hormonal factors, the regulation of phosphoenolpyruvate carboxykinase can be accomplished by glucose itself, inadequate concentrations of it resulting in the induction of the enzyme. The mediator in this regulation, as in hormonal regulation, seems to be cyclic AMP.
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PMID:Stimulation of phosphoenolpyruvate carboxykinase (guanosine triphosphate) activity by low concentrations of circulating glucose in perfused rat liver. 17 1

Cadmium, in addition to producing a variety of toxic manifestations, is known to accumulate in certain "target" organs which include liver and kidney where histological and functional damage becomes apparent. The daily intraperitoneal injection of cadmium chloride for 21 or 45 days stimulated the activities of hepatic pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1, 6-diphosphatase and glucose-6-phosphatase elevated blood glucose and urea, and lowered hepatic glycogen in rats. Whereas chronic Cd treatment failed to alter adenosine-3', 5'-monophosphate phosphodiesterase (PDE) activity, cyclic AMP (cAMY and the activity of basal and fluoride-stimulated forms of hepatic adenylate cyclase (AC) were markedly increased. However, the cAMP binding to hepatic protein kinase was decreased as was the kinase activity ration. An acute dose of Cd decreased hepatic glycogen content and increased blood glucose, serum urea, and hepatic cAMP. Chronic exposure to Cd induced adrenal hypertrophy and augmented adrenal norepinephrine and epinephrine as well as the activity of adrenal tyrosine hydroxylase. This treatment decreased prostatic and testicular weights of mature rats. Although cAMP as well as AC activity of the prostate gland were reduced, cAMP binding to the prostatic protein kinase was increased as was the activity of the cAMP-dependent form of the enzyme. Testicular AC and PDE activities, however, were stimulated, although cAMP remained unaffected. Whereas the activities of the cAMP-dependent and the independent forms of testicular protein kinase were significantly depressed, the binding of cAMP to protein kinase from testes of Cd-treated rats was not affected. In most cases, the observed metabolic alterations persisted up to 28 days on cessation of Cd administration. Subacute Cd treatment suppressed pancreatic function as evidenced by lowered serum immunoreactive insulin (IRI) in presence of hyperglycemia, as well as by partial inhibition of phentolamine-stimulated increases in serum IRI. Although chronic Cd treatment failed to alter the concentration of brain stem norepinephrine and cerebrocortical acetylcholine esterase activity, serotonin levels of brain stem were depressed and the concentration of striatal dopamine and cerebrocortical acetylcholine were significantly elevated when compared with the values seen in control nonexposed animals.
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PMID:Aspects of the biochemical toxicology of cadmium. 17 84

A variety of 6- and 8-substituted analogs of cAMP (cyclic adenosine 3:5-monophosphate) have been tested for their ability to increase activity of tyrosine aminotransferase (EC 2.6.1.5) in cultured Reuber H35 hepatoma cells. Some analogs, particularly the 8-thio-substituted ones, produced effects approximately equivalent to those generated by N-6, O2'-dibutyryl cAMP. In contrast, cAMP and its O-2-monobutyryl derivative were relatively ineffective even at very high concentrations, whereas three other analogs actually depressed the activity of the aminotransferase. Changes in enzyme activity generated by the various analogs were paralleled closely by changes in the relative rate of aminotransferase synthesis. An excellent correlation was found to exist between the ability of any given analog to influence the activity of tyrosine aminotransferase and that of phosphoenolpyruvate carboxykinase (EC 4.1.1.32). A similar correlation was found to exist between the ability of various analogs to evelate the activity of these enzymes and to inhibit reversibly the growth of H35 cells. Only one of five inhibitors of cAMP phosphodiesterase activity tested produce any increase in aminotransferase activity when added alone. All of the 6- and 8-substituted analogs tested, including noniducers, stimulated f1 histone phosphorylation in crude rat liver extracts with approximately equal potencies. On the other hand, dibutyryl cAMP was only a weak activator of protein kinase in vitro, even though it is a potent enzyme inducer. A possible resolution of this apparent discrepancy has been provided by preliminary analyses of site-specific f1 histone phosphorylation in whole cells. Only compounds active as aminotransferase inducers are capable of stimulating phosphorylation of the serine-37 residue of endogenous f1 histone (3- to 10-fold).
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PMID:Effects of 6- and 8-substituted analogs of adenosine 3':5'-monophosphate on phosphoenolpyruvate carboxykinase and tyrosine aminotransferase in hepatoma cell cultures. 23 87

Cyclic AMP plays a major, if not primary, role in the regulation of hepatic gluconeogenesis. The cyclic nucleotide acts on two levels. First, cAMP levels determine the phosphorylation state of key regulatory enzymes including pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Regulation of cAMP levels by glucagon, insulin, and catecholamines accounts in large part for minute-to-minute hormonal control of pathway flux in fed animals and during the transition from fed to starved; second, cAMP plays a key role in regulation of gene transcription of phosphoenolpyruvate carboxykinase, pyruvate kinase, glucokinase, and probably 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Cyclic AMP acts to induce synthesis of mRNA for phosphoenolpyruvate carboxykinase and probably fructose 1, 6-bisphosphatase while it suppresses transcription of the genes for pyruvate kinase and glucokinase. Its role in the regulation of gene transcription of the bifunctional enzyme and 6-phosphofructo 1-kinase remains to be defined. Insulin is the most important hormone for restraining the level of cAMP. Insulin acts to oppose the acute actions of cAMP on enzyme phosphorylation, presumably by activating a phosphodiesterase and thereby lowering cAMP levels. Insulin also opposes the action of hormones (alpha-adrenergic agonists, angiotensin, vasopressin) that act in liver via cAMP-independent phosphorylation. However, in the systems in which this has been studied, the cAMP-independent effects on gluconeogenic/glycolytic pathway flux are small in comparison to cAMP-dependent regulation. Insulin also opposes the action of cAMP on gene transcription by an as yet unknown mechanism. This effect does not appear to involve changes in the level of cAMP because the hormone also acts in cultured cells when added alone or in the presence of dexamethasone. The ability of insulin to lower hepatic cAMP levels and to modulate gene expression are important because restoration of acute regulatory hormone responsiveness to starved or diabetic animals could not occur if insulin were unable to lower cAMP levels and be the dominant factor in modulating the gene expression of these key regulatory enzymes. Clearly, the hepatic gluconeogenic/glycolytic pathway undergoes a complex but extremely well-integrated regulation by hormones that accounts in large part for the major role the organ plays in the control of glucose homeostasis.
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PMID:The role of cyclic AMP in rapid and long-term regulation of gluconeogenesis and glycolysis. 285 23

The possibility whether alterations in the cyclic AMP-adenylate cyclase-phosphodiesterase system play a role in the action of 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (DDT) on hepatic and renal carbohydrate metabolism was investigated. Administration of exogenous cyclic AMP (10mg/100g) was found to mimic the action of DDT which enhanced the activities of pyruvate carboxylase, phosphoenolpyruvate carboxylase, fructose 1,6-diphosphatase and glucose 6-phosphatase in both liver and kidney cortex, elevated the concentration of blood glucose and urea and decreased the amount of hepatic glycogen. Treatment with theophylline augmented the effects of a submaximal dose of this halogenated hydrocarbon on serum urea and glucose as well as the key gluconeogenic enzymes in liver and kidney cortex. Addition of DDT in vitro to liver and kidney homogenates resulted in a significant enhancement of adenylate cyclase activity. Hepatic and renal slices from rats already treated with DDT displayed an increased ability to convert [(3)H]adenosine into cyclic [(3)H]AMP. Whereas kidney-cortex slices excised from rats given caffeine and DDT produced an even greater amount of cyclic [(3)H]AMP, imidazole, propranolol and hydrazine prevented the insecticide-stimulated rise in cyclic nucleotide production. In contrast, prostaglandin E(1) failed to exert any significant effect on DDT-induced increases in cyclic [(3)H]AMP synthesis from radioactive adenosine. The present study and our previous findings (Kacew & Singhal, 1973e) support the concept that the DDT-induced alterations in carbohydrate metabolism of liver and kidney cortex may be related to an initial stimulation of the cyclic AMP-adenylate cyclase system in these tissues.
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PMID:Role of cyclic adenosine 3':5'-monophosphate in the action of 1,1,1-trichloro-2,2-bis-(p-chlorophenyl)ethane (DDT)on hepatic and renal metabolism. 437 84

Isolated rat liver cells maintained in suspension culture for 4 to 5 h synthesize the gluconeogenic cytosolic enzyme phosphoenolpyruvate carboxykinase at a rate approximately 5-fold lower than the in vivo hepatic rate. Glucagon rapidly re-induces phosphoenolpyruvate carboxykinase synthesis in such cells. The rate of enzyme synthesis doubles in 40 min and plateaus at a level 6- to 13-fold higher than in control cells 120 min after glucagon addition at maximal concentration. Consistent with the presumed role of cyclic AMP as a mediator of enzyme induction, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, added simultaneously with glucagon, shifts the hormone dose-response curve 2 log units to the left. Moreover, cyclic AMP supplied exogenously to the cells mimics the inductive effect of glucagon. Total cellular RNA isolated from hepatocytes induced by glucagon contains an increased level of mRNA coding for phosphoenolpyruvate carboxykinase, as determined by translational assay. The kinetics and extent of the rise in mRNA level are adequate to explain the stimulation of enzyme synthesis. Although glucagon on its own induces a build-up of phosphoenolpyruvate carboxykinase mRNA and a commensurate stimulation of enzyme synthesis, the glucagon induction is very markedly amplified when the cells are first preincubated with dexamethasone. The glucocorticoid by itself, however, does not have any substantial effect on the level of phosphoenolpyruvate carboxykinase mRNA or on the rate of enzyme synthesis. Its role can therefore be characterized as permissive.
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PMID:Regulation of phosphoenolpyruvate carboxykinase (GTP) synthesis in rat liver cells. Rapid induction of specific mRNA by glucagon or cyclic AMP and permissive effect of dexamethasone. 629 90

We engineered a hepatoma cell line that produces an up-regulation of insulin in response to cAMP, dexamethasone, and retinoic acid, and a down-regulation in response to insulin. We devised a regulatory secretion system by placing proinsulin DNA under the regulatable promoter for phosphoenolpyruvate carboxykinase (PEPCK). To assess the ability to regulate insulin secretion, we used the rat hepatoma cell line, H4IIE. The H4IIE cells secreted immunoreactive insulin (IRI) constantly at a level of 1-3 fmol/10(6) cells/h. IRI increased approximately two-fold upon stimulation with 0.5 mM cAMP and five-fold with the addition of the cAMP-dependent phosphodiesterase inhibitor IBMX, as compared to baseline IRI secretion. IRI increased 18-fold by 1-500 nM dexamethasone together with cAMP and IBMX. Addition of exogenous insulin to the culture medium significantly decreased insulin mRNA expression on Northern blot.
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PMID:Regulatable production of mature insulin from a hepatocyte cell line: insulin production is up-regulated by cAMP and glucocorticoids, and down-regulated by insulin. 898 Jan 15

In cultured rat hepatocytes, the gluconeogenic key enzyme, phosphoenolpyruvate carboxykinase (PCK), is induced by glucagon via elevation of cyclic 3',5' adenosine monophosphate (cAMP). The proinflammatory cytokine, interleukin-6 (IL-6), which in the liver together with IL-1beta and tumor necrosis factor alpha triggers the acute-phase response, had been shown to attenuate the glucagon-induced increase in PCK gene transcription, messenger (mRNA) levels, and enzyme activity. The molecular mechanism of this inhibition was investigated in the present study. Glucagon increased cyclic cAMP and PCK mRNA levels to a transient maximum twofold and fivefold, respectively. The increases were attenuated by IL-6. Forskolin, which stimulates adenylate cyclase activity, increased cAMP and PCK mRNA levels 1.6-fold and fivefold, respectively. However, IL-6 attenuated the forskolin-stimulated increase in PCK mRNA but not the increase in cAMP. This showed that IL-6 inhibited PCK mRNA increase in part by the attenuation of cAMP increase, but also beyond cAMP formation. This was confirmed in experiments in which PCK mRNA levels were increased by the nonhydrolyzable cAMP-analogue, chlorophenylthio (CPT)-cAMP. The increase in PCK mRNA was again attenuated by IL-6. In pertussis toxin- and in isobutylmethylxanthine-treated hepatocytes, IL-6 still inhibited the glucagon-stimulated increase in cAMP, indicating that IL-6 did not activate an inhibitory G-protein or phosphodiesterase, which could cause the impairment of cAMP increase. To demonstrate whether the inhibition of PCK gene expression by IL-6 beyond cAMP might be caused by the inhibition of the activation of the PCK gene promoter by cAMP, cultured rat hepatocytes were transfected with a luciferase reporter gene construct under the control of a PCK gene promoter fragment (base -979 to base +32). Luciferase activity was determined after stimulation of the cells with CPT-cAMP in the absence or presence of IL-6. CPT-cAMP increased luciferase activity by 1.7-fold, which was inhibited in the presence of IL-6. It is concluded that IL-6 had a dual inhibitory effect on the stimulation of PCK gene expression by glucagon. It inhibited the increase in cAMP at a site before cAMP formation by adenylate cyclase and at a site after cAMP formation, the activation of the PCK gene promoter by cAMP.
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PMID:Mechanism of the impairment of the glucagon-stimulated phosphoenolpyruvate carboxykinase gene expression by interleukin-6 in rat hepatocytes: inhibition of the increase in cyclic 3',5' adenosine monophosphate and the downstream cyclic 3',5' adenosine monophosphate action. 921 54

To utilize hepatocytes for insulin-producing surrogate cells, we devised a regulatory secretion system by placing proinsulin DNA under the regulatable promoter for phosphoenolpyruvate carboxykinase (PEPCK). The expression of PEPCK is down-regulated by insulin, and up-regulated by cAMP and glucagon. To express insulin in hepatocytes, we constructed an adenoviral insulin expression system. After infection, the hepatocytes secreted immunoreactive insulin (IRI) at an increasing rate. IRI secretion increased over four-fold upon stimulation with 300 microM cAMP and 500 microM of the cAMP-dependent phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). This increase was also observed with glucagon and IBMX. Production was augmented two-fold by the addition of wortmannin, phosphatidylinositol (PI)-3-kinase inhibitor, suggesting that inhibitory insulin signaling to the PEPCK promoter may be mediated through PI-3-kinase. Addition of exogenous insulin to the culture decreased insulin mRNA expression remarkably on Northern blot. Thus, by using a PEPCK promoter for insulin expression, we were able to up-regulate insulin production from hepatocytes with cAMP and glucagon, and down-regulate with insulin itself.
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PMID:Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin. 981 59


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