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)

Induction of delta-aminolevulinic acid synthetase by allylisopropylacetamide in organ-cultured chick embryo liver was not appreciably influenced by any of cycli AMP, dibutyryl cyclic AMP, theophylline, glucose, insulin, glucagon, epinephrine, isoproterenol, and hydrocortisone, whereas the activity of tyrosine aminotransferase significantly increased in response to cyclic AMP and some of those hormones. Accumulation of delta-aminolevulinic acid synthetase in the cultured liver cytosol fraction was not appreciably increased by the addition of dibutyryl cyclic AMP or insulin to the incubation medium. Apparently the behaviors of the induction of delta-aminolevulinic acid synthetase in chick embryo liver in ovo and in vitro differ from those in the livers of adult chicken and rat. High concentrations of chloramphenicol suppressed significantly the allylisopropylacetamide-induced increase of delta-aminolevulinic acid synthetase as well as incorporation of 14C-leucine into proteins. The activity of tyrosine aminotransferase, however, was rather increased when relatively low concentrations of chloramphenicol were added to the medium.
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PMID:Comparative studies of the effects of cyclic AMP, various hormones and chloramphenicol on the induction of delta-aminolevulinic acid synthetase and tyrosine aminotransferase in the organ-cultured chick embryo liver. 1 73

Drug-induced porphyrin accumulation occurs in chick embryo liver cells maintained in serum-free Waymouth MD 705/1 medium. Addition of insulin and thyroxine to the medium results in a marked enhancement of porphyrin accumulation. The addition of hydrocortisone results in a further enhancement of porphyrine accumulation. Several agents which are reported to increase intracellular adenosine 3':5'-monophosphate (cAMP) levels, viz. glucagon, sodium fluoride, cAMP or its dibutyryl derivative, 3-isobutyl-1-methylxanthine and papaverine enhanced drug-induced porphyrin biosynthesis. On the other have, agents which are reported to decrease intra-cellular cAMP levels, viz. alloxan and imidazole, diminished drug-induced porphyrin accumulation. cAMP appears to enhance, but not to function as a "second messenger" in drug-induced porphyrin biosynthesis. Drug-induced porphyrin accumulation in chick embryo liver cells depend upon the insulin to glucagon ratio. A low level of porphyrin accumulation occurs at insulin to glucagon ratios similar to those found following glucose administration in vivo, suggesting a possible explanation for the therapeutic effect of glucose in hepatic porphyria. The 5 alpha A(A:B trans) and 5 beta H(A:Bcis) steroids are equipotent in inducing delta-aminolevulinic acid synthetase and porphyrin accumulation in chick embryo liver cells maintained in serum-free culture medium. Thus, there is no specific steric requirement for porphyrin-inducing activity in steroids.
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PMID:Hormonal effects on the regulation of hepatic heme biosynthesis. 8 65

Primary liver cells, isolated from 16- 17-day-old chick embryos, were incubated in a serum-free chemically defined medium (Ham's F12) supplemented with hormones for up to 6 days. The culture method also includes the complete removal of contaminating red cells before the initiation of culture. On the 2nd day in cluture, the level of amino-levulinate (ALA) synthase activity in response to allylisopropylacetamide (AIA) was increased 6-fold in cells grown in F12. Insulin, hydrocortisone, and triiodothyronine alone had no appreciable effects on ALA synthase levels. On the other hand, when added with AIA, insulin, insulin plus hydrocortisone, insulin plus hydrocortisone triiodothyronine increased ALA synthase levels 17-, 50-, 110-fold, respectively. The maximally induced levels of ALA synthase activity by AIA in the presence of insulin, hydrocortisone, and triiodothyronine were approximately 15 nmol of ALA/mg of protein/h, 37 degrees or 3 micronmol of ALA/g of tissue/h, 37 degrees, a value similar to that found in ovo or at least 5 times greater than that found in rat liver. The morphology of hepatocytes was maintained for at least 6 days in culture, although the induction of ALA synthase was reduced after the 4th day unless triiodothyronine was present. Dibutyryl adenosine 3':5'-monophosphate (10(8) M) or glucagon (5x10(8) M) had little effect on the induced as well as noninduced levels of ALA synthase or porphyrins. These data demonstrate a "permissive" effect of insulin, hydrocortisone, and triiodothyronine on the induction of ALA synthase and porphyrins by AIA in cultured chick embryo liver cells. In the absence of insulin hydrocortisone, or triiodothyronine, AIA produces only a slight increase in ALA synthase activity or porphyrins (or both); on the other hand, it produces a marked increase in the enzyme activity and porphyrins when these hormones are added to the culture medium. The term "permissive" is applied to these hormone-dependent effects. A sensitive spectrofluorometric method for heme quantitation allowed us to follow changes in the cellular heme content in hemoglobin-free cultured liver cells. Heme content in the cultured liver cells was approximately 250 pmol/mg of protein at the initiation of culture but gradually declined to 175 pmol/mg of protein at the initiation of culture but gradually declined to 175 pmol/mg of protein during 48 h of incubation. The apparent decrease in heme content may be accounted for by the concomitant increase in protein content in these cells.
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PMID:Induction of aminolevulinate synthase and porphyrins in cultured liver cells maintained in chemically defined medium. Permissive effects of hormones on induction process. 32 58

In the present work we demonstrate that insulin decreases the phenobarbital-induced activities of delta-aminolevulinic acid synthase and ferrochelatase in isolated hepatocytes from normal and experimental-diabetic rats. Insulin concentrations required to produce significant inhibition in diabetic hepatocytes were higher than in normal cells. Under similar experimental conditions, insulin decreased the basal activities of delta-aminolevulinic acid synthase and ferrochelatase in hepatocytes from normal rats; no inhibitory effect was observed on the basal activity of delta-aminolevulinic acid synthase in hepatocytes from diabetic rats. Cytochrome P-450 content of both normal and diabetic cells was not affected by insulin in absence or presence of phenobarbital. The inhibitory action of insulin was exerted even when effective concentrations of glucagon, dexamethasone, or 8-(p-chlorophenylthio)-cAMP were present.
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PMID:Studies on regulatory mechanisms of heme biosynthesis in hepatocytes from normal and experimental-diabetic rats. Role of insulin. 216 18

Cyclic AMP-dependent protein kinases I and II, partially purified from rat liver cytosol, were inhibited 50% by 40 microM hemin and 100 microM hemin, respectively. With the purified catalytic subunit of cyclic AMP-dependent protein kinase, hemin caused non-competitive inhibition with respect to the peptide substrate and mixed inhibition with respect to ATP. Hemin also inhibited purified phosphorylase b kinase, indicating that hemin concentrations above 10 microM markedly inhibit multiple protein kinases. In isolated intact hepatocytes, hemin inhibited the glucagon-dependent activation of cyclic AMP-dependent protein kinases and the activation of glycogen phosphorylase. For both effects, high heme concentrations (40-60 microM) were required for 50% inhibition. Similar high levels of exogenous hemin inhibited total hepatocyte protein synthesis. By contrast, 5 microM hemin or less was sufficient to raise intracellular heme levels, as indicated by the relative heme-saturation of tryptophan oxygenase in hepatocytes. Hemin, 5 microM, completely repressed induction of 5-aminolevulinate synthase by dexamethasone in hepatocyte primary cultures. Such repression is unlikely to be mediated by inhibition of protein kinases.
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PMID:Effects of hemin on rat liver cyclic AMP-dependent protein kinases in cell extracts and intact hepatocytes. 299 84

Glucagon elicits a twofold increase in delta-aminolevulinic acid synthetase activity in the livers of 18-day-old chick embryos. This rise occurs when RNA synthesis is inhibited, but is prevented when protein synthesis is blocked. Cyclic adenosine monophosphate appears not to be involved.
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PMID:Delta-aminolevulinic acid synthetase: induction in embryonic chick liver by glucagon. 431

Addition of glucose to cultured chick embryo hepatocytes caused a concentration-dependent impairment of phenobarbital-mediated induction of delta-aminolevulinate (ALA) synthase resembling the "glucose effect" observed in rodents in vivo. This glucose effect occurred in the complete absence of extrahepatic factors such as serum and hormones. Fructose, glycerol, and lactate mimicked the inhibitory glucose effect on ALA synthase induction, whereas 2-deoxyglucose and 3-O-methylglucose augmented the induction evoked by phenobarbital. 2-Deoxyglucose reversed the effect of glucose, glycerol, and lactate on ALA synthase induction suggesting that the glucose effect is mediated by free glucose or glucose 6-phosphate or a nonglycolytic metabolite of glucose 6-phosphate. The phenobarbital-mediated induction of cytochrome P-450 hemoprotein(s) and its monooxygenase function were concomitantly diminished by glucose. However, this inhibitory effect or glucose was reversible by the addition of exogenous heme or ALA suggesting that the primary target of the glucose effect is ALA synthase induction and not synthesis of apocytochrome P-450. Glucagon and dibutyryl cAMP enhanced the induction of ALA synthase and cytochrome P-450 by phenobarbital and partially counteracted the glucose effect on both enzymes suggesting that the glucose effect may be mediated by changes in cAMP levels. Although insulin did not alter induction of ALA synthase, it impaired induction of cytochrome P-450 even in the presence of glucagon and cAMP. These data may be relevant for the treatment with glucose and heme of patients with "inducible" hepatic porphyria.
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PMID:Induction of delta-aminolevulinate synthase and cytochrome P-450 hemoproteins in hepatocyte culture. Effect of glucose and hormones. 627 Jan 45

If I were living in Caucasus I would be writing fairy tales there Chekov, 1888 The question of the reasons for the extreme variation in morbidity among the gene carriers of acute porphyria and the great diversity of the precipitating factors are approached by the aid of a model of interacting genomic circuits. It is based on the current paradigm of the acute porphyric attack as a result of a toxic proximal overload of the enzyme-deficient heme-biosynthetic patway. Porphyrogenic influx of precursors is seen as a consequence of uncontrolled induction of its gate-keeping enzyme, ubiquitous 5-aminolevulinate synthase (ALAS1), due to attenuated post-translational control of the enzyme combined with activated gene transcription. Focus is directed on the genomic control of the master-regulator of ALAS1-transcription, the nuclear receptor pair constitutively active receptor (CAR) and pregnane xenobiotic receptor (PXR). On activation by their ligands, i.e. lipophilic drugs, solvents, alcohols, hormonal steroids and biocides, these DNA-binding proteins transform xenobiotic or steroid stimuli to coordinated activations of gene transcription-programs for ALAS1 and apo-cytochromes P450 (apo-CYPs), thus effecting the formation of xenobiotic-metabolizing cytochrome P450 enzymes. The potency of the CAR/PXR-transduction axis is enhanced by co-activators generated in at least four other genomic circuits, each triggered by different external and internal stimuli clinically experienced to be porphyrogenic, and each controlled by co-activating and co-repressing modulators. The expressions of the genes for CAR and PXR are thus augmented by binding glucocorticoid receptor (GR) activated by a steroid hormone, e.g, cortisol generated in fasting, infection or different forms of stress. The promotor regions of ALAS1 and apoCYPs contain binding sites for at least three co-activating transcription factors enhancing CAR/PXR transduction: i.e. the ligand-independent growth hormone (GH)-pulse controlled hepatocyte nuclear factor 4 (HNF4), the insulin-responsive forkhead box class O-(FOXO) protein pathway activated in stress and infection, and the proliferator-activated receptor gamma co-activator 1 alpha (PGC-1alpha) circuit responding to glucagon liberated in fasting. Many interactions and cross-talk take place within the tangle of genomic circuits that control ALAS1-transcription, which may explain the extreme inter- and intra-individual variability in morbidity in acute porphyria. Reasons for gender-differences are found in sex-dependent control of HPA- and GH-activity as well as in direct, or GR-mediated effects on CAR/PCR activation. Constitutional differences in individual porphyric morbidity may be discussed along lines of mutations or duplications of genes for co-activating or co-repressing nuclear proteins active at different levels within the circuits.
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PMID:(Far) Outside the box: genomic approach to acute porphyria. 1729 22