Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In primary cultures of rat hepatocytes, addition of dexamethasone (10 microM) plus glucagon (0.5 microM) caused several-fold increases in the activities of serine dehydratase (EC 4.2.1.13), tryptophan oxygenase (EC 1.13.11.11), and tyrosine aminotransferase (EC 2.6.1.5) in 24 h. These inductions were inhibited by insulin. Addition of epinephrine or phenylephrine at 10 microM blocked these inductions. This suppressive effect of adrenergic compounds was completely abolished by the alpha-adrenergic antagonist phenoxybenzamine at 10 microM. Immunochemical analysis with antiserum to serine dehydratase showed that the changes in enzyme activity were due to changes in the amount of enzyme. Epinephrine was effective even when glucagon was replaced by dibutyryl cAMP (50 microM), indicating that alpha-adrenergic suppression of enzyme inductions was mediated by a cAMP-independent mechanism. Furthermore, the findings that prazosin antagonized this epinephrine effect, but yohimbine did not, indicate that the alpha 1- but not the alpha 2-receptor is involved in this inhibition. However, the alpha-adrenergic effect was different from that of insulin in that, unlike the latter, the inductions of tryptophan oxygenase and tyrosine amino-transferase by dexamethasone alone were not inhibited. The alpha-adrenergic action apparently counteracts the action of glucagon and cAMP. For determination of the beta-adrenergic effect of catecholamines on the inductions of enzymes, beta-adrenergic compounds were tested without glucagon. Isoproterenol or epinephrine plus phenoxybenzamine induced tryptophan oxygenase and tyrosine aminotransferase. Induction of serine dehydratase was shown by isoproterenol only in the presence of 1-methyl-3-isobutylxanthine, an inhibitor of phosphodiesterase. These results indicate that catecholamines play dual roles in regulation of the amount of enzyme through their alpha 1- and beta-adrenergic actions.
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PMID:alpha-Adrenergic regulation of enzymes of amino acid metabolism in primary cultures of adult rat hepatocytes. 613 92

The genes for tryptophan oxygenase (TO) and tyrosine aminotransferase (TAT) are expressed in a tissue- and development-specific manner and are regulated by glucocorticoids (TO and TAT) and glucagon or its intracellular mediator cAMP (TAT) in rat liver. We have analyzed the chromatin structure of these genes in the vicinity of the 5' ends with regard to DNaseI hypersensitivity and have found DNaseI hypersensitive sites upstream of each of the promoters. Mapping of this region reveals three closely spaced cleavage sites near the TO promoter and a doublet of sites near the TAT promoter. In both genes additional cleavage sites are found further upstream. All hypersensitive sites of both genes are absent in kidney nuclei and therefore appear to be specific for the tissue expressing the genes. A correlation of expression and modified chromatin structure was also observed in a hepatoma cell line expressing TAT but not TO: hypersensitive sites are present in TAT but not in TO chromatin. Upon glucocorticoid induction an additional hypersensitive site is detected approximately 2 kb upstream of the TAT promoter in liver and hepatoma cells.
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PMID:Tissue-specific DNaseI hypersensitive sites in the 5'-flanking sequences of the tryptophan oxygenase and the tyrosine aminotransferase genes. 614 20

The basal activity of tryptophan 2,3-dioxygenase (EC-1.13.11.11) in primary cultured rat hepatocytes decreased during culture, but addition of either tryptophan (2.5 x 10(-3) M) or dexamethasone (1 x 10(-6) M) could prevent the decrease. Addition of both compounds caused severalfold induction of activity. Glucagon (1 x 10(-8) M) alone did not induce the activity, but its inductive effect in combination with tryptophan was similar to that of tryptophan plus dexamethasone. The effect of glucagon was additive with those of tryptophan and dexamethasone and hence the highest induction (7-fold) was achieved by addition of all three inducers. Glucagon could be replaced by dibutyryl cyclic AMP (1 x 10(-5) M). Insulin (1 x 10(-8) M) inhibited the inductions by glucagon and dexamethasone, but not that by tryptophan. Cycloheximide inhibited the inductions by all three inducers, but actinomycin D inhibited only the induction by dexamethasone. These results suggest that the three compounds have different mechanisms of induction of tryptophan oxygenase activity: tryptophan prevents enzyme inactivation, dexamethasone may stimulate enzyme synthesis at the level of transcription, and glucagon may enhance the synthesis at the translational level.
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PMID:Insulin and glucagon as a new regulator system for tryptophan oxygenase activity demonstrated in primary cultured rat hepatocytes. 624 4

Tryptophan 2,3-dioxygenase [EC 1.13.11.11] in primary cultures of adult rat hepatocytes was induced 3-4 fold by 1 microM dexamethasone and 6-7 fold by dexamethasone plus glucagon (0.1 microM). Changes of the enzyme activity, amount of enzyme, measured by immunotitration, and rate of enzyme synthesis, assayed by measurement of [3H]leucine incorporation into the enzyme protein, were closely correlated. Furthermore, in a reticulocyte lysate system for cell-free protein synthesis, mRNA of the enzyme was translated to the protein corresponding to the subunit of tryptophan 2,3-dioxygenase, which was identified by SDS-polyacrylamide gel electrophoresis. The activity of translatable mRNA of the enzyme was increased more than 10-fold by dexamethasone and its final content in total mRNA was 0.34%. Glucagon alone did not increase mRNA activity, but dexamethasone plus glucagon increased mRNA activity to twice that with dexamethasone alone, the maximal content of the mRNA being 0.77% of the total mRNA content 12 h after addition of hormones. Insulin (0.1 microM) caused 75% inhibition of the maximum increase of mRNA activity of the enzyme induced by dexamethasone and glucagon. Epinephrine (10 microM) also caused 58% inhibition of the maximum increase. Insulin and epinephrine also suppressed increase of mRNA of tryptophan 2,3-dioxygenase induced by dexamethasone alone. Therefore, dexamethasone alone or together with glucagon stimulated transcription of tryptophan 2,3-dioxygenase increasing its mRNA and enzyme synthesis in hepatocytes. Conversely, insulin and epinephrine suppressed these increases of mRNA synthesis and thus decreased enzyme synthesis.
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PMID:Hormonal regulation of translatable mRNA of tryptophan 2,3-dioxygenase in primary cultures of adult rat hepatocytes. 636 Oct 14

The plasma levels of corticosterone, insulin and glucagon, and the concomitant changes in the levels of several liver enzymes and metabolites were measured in intact rats in the basal state during 24 hours and under conditions of food deprivation and hypoxia. The levels of the following enzymes and metabolites were examined: phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, pyruvate kinase, phosphofructokinase, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, glucose, glucose-6-phosphate, glycogen, fructose-6-phosphate, hexokinase, tyrosine amino-transferase and tryptophan oxygenase. During food deprivation, the increased gluconeogenesis is possibly a result of glucagon activity. In contrast, however, during hypoxia the increase in gluconeogenesis seems to be a result of the higher plasma level of corticosterone. During starvation, the insulin concentration dropped steadily and came close to zero.
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PMID:Plasma concentrations of glucose, corticosterone, glucagon and insulin and liver content of metabolic substrates and enzymes during starvation and additional hypoxia in the rat. 703 Aug 99

Serum at 5 to 10% is required for maintenance of functional adult rat hepatocytes in primary culture. One effect of the serum is to induce attachment and spreading of hepatocytes on plates as monolayers. Another role is to maintain cell viability for over 2 days. For the first effect, serum could be replaced completely by fibronectin (Fn). The effects of Fn on attachment and spreading of cells were dose-dependent and maximum at 10 micrograms/ml. Cells in serum-free medium on Fn-coated dishes showed similar activities of glycogenolysis and glycogenesis to cells cultured in medium containing 5% calf serum on untreated dishes in response to glucagon, dibutyryl cyclic AMP (bt2c AMP), isoproterenol and insulin. The increase in alkaline phosphatase [EC 3.1.3.1] activity and induction of tyrosine aminotransferase [EC 2.6.1.5] by dexamethasone (Dex) in cells under the two conditions were also similar. However, the inductions of tryptophan oxygenase [EC 1.13.11.11] by Dex, glucagon, and bt2cAMP were 4-7 times higher in cells cultured in serum-free medium. The inductions by Dex plus glucagon in the two types of cultures were inhibited similarly by insulin. In serum-free medium containing Dex and insulin in Fn-coated dishes, the cells survived as monolayers for about 50 h without detachment from the dishes, but for longer survival it was necessary to add 5% serum to the medium. A fraction with a molecular weight of over 50,000 from serum was separated by ultrafiltration and this fraction showed a similar effect to serum in increasing survival. A similar factor, but with about 70 times higher specific activity, was found in an extract of bovine pituitary gland.
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PMID:Role of serum in maintenance of functional hepatocytes in primary culture. 716 Dec 70

Developmental increase of tryptophan oxygenase (L-tryptophan: oxygen 2, 3-oxidoreductase (decyclizing), EC 1.13.11.11) was studied using hepatocytes of neonatal rats in primary culture. Hepatocytes from rats of 2-30-days-old were isolated and cultured for 2 days. In cultured hepatocytes of 2-day-old rats, tryptophan (2.5 mM), dexamethasone (1 x 10(-5) M) and glucagon (1 x 10(-7) M) did not cause the appearance of tryptophan oxygenase. But the enzyme activity became detectable, when hepatocytes from 5-day-old rats were incubated with tryptophan, the oxygenase could be induced precociously by dexamethasone, but by glucagon. The effect of glucagon was first seen 2 weeks after birth. However, in hepatocytes of 9-day-old rats glucagon stimulated formation of cyclic AMP and protein kinase activity (EC 2.7.1.37) and also induced tyrosine aminotransferase (EC 2.6.1.5). When hepatocytes of 9-day-old rats were cultured for 4 days, their tryptophan oxygenase became inducible by glucagon. Insulin almost completely inhibited precocious appearance of the enzyme activity evoked by tryptophan plus dexamethasone in hepatocytes of 9-day-old rats. These studies suggest that the appearance of tryptophan oxygenase in rat liver during development is due to first the onset of gene coding for tryptophan oxygenase and then stimulation by the sequential actions of glucocorticoid and glucagon.
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PMID:Hormonal control of the development of tryptophan oxygenase in primary cultures of young rat hepatocytes. 730 79

We have previously shown that the rate of hepatic gluconeogenesis is reduced in TCDD-treated rats and that this decrease in carbohydrate production is associated with a dose-dependent reduction of the activity of PEPCK, the rate limiting enzyme of gluconeogenesis. This derailment of glucose metabolism has been suggested to be the critical lesion in acute TCDD toxicity. To further elucidate the mechanism of decreased PEPCK activity we performed Northern blot analyses using a cDNA probe complementary to a portion of the mRNA coding for PEPCK. We have demonstrated that 4 and 8 days after TCDD treatment (125 micrograms/kg, p.o.) liver PEPCK mRNA in Sprague-Dawley rats was decreased to very low levels as compared to vehicle-treated and pair-fed control animals. This decline of PEPCK mRNA was paralleled by decreased levels of PEPCK protein, as revealed by Western blot analyses and was accompanied by a reduction in the enzymatic activity of PEPCK. These results indicate that the decrease of PEPCK activity by TCDD is most likely the result of decreased expression of the PEPCK gene. These together with previous results also suggest that many of the physiological responses occurring in TCDD-treated animals (reduced feed intake, decreased insulin, increased corticosterone, increased glucagon and cAMP levels) which would normally stimulate PEPCK gene expression, are ineffective. Furthermore tryptophan 2,3-dioxygenase (TdO) activity, which is regulated in a very similar fashion to PEPCK activity, is also reduced after TCDD treatment, suggesting a common mechanism by which TCDD alters the regulation of these enzymes. P-450 1A1 mRNA and related EROD activity were maximally induced under the conditions of these experiments and represent a positive control for TCDD-related alterations of gene expression. However, because of differences in the dose-response characteristics of TCDD-induced reduction of PEPCK activity and induction of EROD activity an involvement of the Ah receptor in the reduction of PEPCK activity cannot be postulated.
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PMID:Reduction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is due to decreased mRNA levels. 847 1

Expression of tryptophan 2,3-dioxygenase (TO) and serine dehydratase (SDH) has not previously been maintained or re-induced in long-term cultured hepatocytes. In the present study, we succeeded in inducing expression of TO and SDH mRNAs in adult rat hepatocytes cultured in serum-free L-15 medium supplemented with epidermal growth factor and 2% dimethyl sulfoxide (DMSO). After the start of culture, the expression of TO mRNA rapidly disappeared and at 96 h it was less than 10% of that at isolation. However, after the addition of 2% DMSO from 96 h, the transcript level gradually increased and reached about 40% of that of the isolated cells at day 14. In addition, the expression of TO mRNA was enhanced in cells treated with both 10(-5) M dexamethasone and 10(-7) M glucagon. In contrast, the expression of SDH mRNA decreased very rapidly and we could not detect it after 24 h of culture. Furthermore, 2% DMSO failed to induce it. However, when both 10(-5) M dexamethasone and 10(-7) M glucagon were added to the culture medium at day 9, we observed dramatic induction of SDH mRNA 24 h later. Primary hepatocytes cultured by this method could express and maintain highly differentiated hepatic functions for a long time. Thus, this in vitro system is suitable for the investigation of hepatic functions.
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PMID:Recovery of mRNA expression of tryptophan 2,3-dioxygenase and serine dehydratase in long-term cultures of primary rat hepatocytes. 890 14

Dietary lipid peroxidation products cause endogenous lipid peroxidation with hepatic dysfunction. In this study, we isolated and cultured hepatocytes of rats that were given secondary autoxidation products of linoleic acid (p.o., 400 mg/rat/day for 3 days), and examined the hormonal responses of these hepatocytes. An increase in thiobarbituric acid reactive substances and a depletion of vitamin E persisted in hepatocytes from treated rats for at least 24 h in culture as compared to those from control rats. As markers for hepatic dysfunction, the activities of six enzymes were measured. In each case, there was an initial decrease in the enzyme activity in hepatocytes from the treated rats, and all activities were restored by 48 h in culture. Then, we measured the hormonal responses of these hepatocytes. The responses to insulin or glucagon in hepatocytes from secondary products-treated and control rats were the same. In contrast, the response to dexamethasone was significantly lowered in hepatocytes from secondary products-treated rats as measured by the induction of tryptophan 2,3-dioxygenase and tyrosine aminotransferase. We conclude that primary cultured hepatocytes from the rats treated in vivo with dietary lipid peroxidation products retained symptoms of oxidative stress and had a low response to glucocorticoids.
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PMID:Effects of dietary lipid peroxidation products on hormonal responses in primary cultured hepatocytes of rats. 943 89


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