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)

We reported that glucagon and phenylephrine decrease hepatocyte GSH by inhibiting gamma-glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis (Lu, S.C., J. Kuhlenkamp, C. Garcia-Ruiz, and N. Kaplowitz. 1991. J. Clin. Invest. 88:260-269). In contrast, we have found that insulin (In, 1 microgram/ml) and hydrocortisone (HC, 50 nM) increased GSH of cultured hepatocytes up to 50-70% (earliest significant change at 6 h) with either methionine or cystine alone as the sole sulfur amino acid in the medium. The effect of In occurred independent of glucose concentration in the medium. Changes in steady-state cellular cysteine levels, cell volume, GSH efflux, or expression of gamma-glutamyl transpeptidase were excluded as possible mechanisms. Both hormones are known to induce cystine/glutamate transport, but this was excluded as the predominant mechanism since the induction in cystine uptake required a lag period of greater than 6 h, and the increase in cell GSH still occurred when cystine uptake was blocked. Assay of GSH synthesis in extracts of detergent-treated cells revealed that In and HC increased the activity of GCS by 45-65% (earliest significant change at 4 h) but not GSH synthetase. In and HC treatment increased the Vmax of GCS by 31-43% with no change in Km. Both the hormone-mediated increase in cell GSH and GCS activity were blocked with either cycloheximide or actinomycin D. Finally, when studied in vivo, streptozotocin-treated diabetic and adrenalectomized rats exhibited lower hepatic GSH levels and GCS activities than respective controls. Both of these abnormalities were prevented with hormone replacement. Thus, both in vitro and in vivo, In and glucocorticoids are required for normal expression of GCS.
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PMID:Insulin and glucocorticoid dependence of hepatic gamma-glutamylcysteine synthetase and glutathione synthesis in the rat. Studies in cultured hepatocytes and in vivo. 135 65

Our present work characterized the role of hormone-mediated signal transduction pathways in regulating hepatic reduced glutathione (GSH) synthesis. Cholera toxin, dibutyryl cAMP (DBcAMP), and glucagon inhibited GSH synthesis in cultured hepatocytes by 25-43%. Cellular cAMP levels exhibited a lower threshold for stimulation of the GSH efflux than inhibition of its synthesis. The effect of DBcAMP was independent of the type of sulfur amino acid precursor and cellular ATP levels and unassociated with increased GSH mixed disulfide formation or altered GSH/oxidized glutathione ratio. In liver cytosols, addition of DBcAMP and cAMP-dependent protein kinase (A-kinase) inhibited GSH synthesis from substrates (cysteine, ATP, glutamate, and glycine) by approximately 20% which was prevented by the A-kinase inhibitor. However, if only substrates of the second step in GSH synthesis were used (gamma-glutamylcysteine, glycine, and ATP), DBcAMP and A-kinase exerted no inhibitory effect. Phenylephrine, vasopressin, and phorbol ester also inhibited GSH synthesis in cultured cells by approximately 20%, and depleted cell GSH independent of the type of sulfur amino acid precursor. Cellular cysteine level was unchanged despite the significant fall in GSH after glucagon or phenylephrine treatment. Pretreatment with either staurosporine, C-kinase inhibitor, or calmidazolium, a calmodulin inhibitor, partially prevented but, together, completely prevented the inhibitory effect of phenylephrine. The same combination had no effect on the inhibitory effect of glucagon. The effects of hormones were confirmed in both the intact perfused liver and after in vivo administration. Thus, two classes of hormones acting through distinct signal transduction pathways may down-regulate hepatic GSH synthesis by phosphorylation of gamma-glutamylcysteine synthetase.
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PMID:Hormone-mediated down-regulation of hepatic glutathione synthesis in the rat. 164 17

Hepatic glutathione concentration is decreased in protein-energy malnutrition. Malnourished rats are able to replenish hepatic glutathione after oral supplementation with L-2-oxothiazolidine-4-carboxylate, a cysteine pro-drug, to levels that are higher than in control rats. These results suggest that, even if a normal amount of amino acids for glutathione synthesis is provided, homeostatic control of glutathione concentration after protein-energy malnutrition is abnormal. The rate limiting enzyme for glutathione synthesis, gamma-glutamylcysteine synthetase, is subject to both short and long term hormonal control. Therefore, we used hepatocytes isolated from weanling rats fed a very low protein diet (0.5 g protein/100 g diet) or a diet adequate in protein for 2 wk to investigate whether a loss of hormonal control could contribute to abnormal regulation of hepatic glutathione. Glutathione concentration in hepatocytes isolated from protein-energy malnourished rats was 82% lower than in controls. In vitro supplementation of isolated hepatocytes with oxothiazolidine-4-carboxylate or methionine increased glutathione concentration in hepatocytes from malnourished rats to concentrations equivalent to control cells. However, when hepatocytes were incubated with cysteine, total glutathione in malnourished rats exceeded that of controls. Treatment of cells from control rats with 50 nmol/L glucagon or 1 mmol/L db-cAMP decreased glutathione concentration by 25-43%. In contrast, the glutathione concentration in hepatocytes of rats fed the low protein diet did not respond to treatment with glucagon or db-cAMP. These data indicate that glutathione synthesis is insensitive to regulation by cAMP in rats with protein-energy malnutrition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of hepatocyte glutathione by amino acid precursors and cAMP in protein-energy malnourished rats. 812 Jun 50

The influences of food deprivation and refeeding on glutathione (GSH) status, antioxidant enzyme activity and lipid peroxidation in response to an acute bout of exercise were investigated in the liver and skeletal muscles of male Sprague-Dawley rats randomly divided into three groups: starved for 48 h without refeeding; starved for 48 h and refed for 24 or 48 h. Half of each group of rats was exercised on a treadmill until exhaustion and killed immediately, whereas the other half group was killed at rest. Food-deprived rats had significantly lower liver GSH concentration and GSH:glutathione disulfide (GSSG) ratio. Malondialdehyde concentrations in the liver and skeletal muscle were both higher in the starved than in the refed rats (P < 0.05). Refed rats had significantly greater liver GSH level, gamma-glutamylcysteine synthetase and glucose 6-phosphate dehydrogenase activities and plasma insulin concentration than unfed rats. Exercised 24- and 48-h refed rats had 27% and 31 % lower liver GSH (P < 0.05), respectively, and a 21 % lower GSH:GSSG ratio (P < 0.05) than their rested counterparts. Plasma insulin concentrations were significantly lower, whereas glucagon concentrations were greater in the exercised than in the rested rats. Muscle GSH concentration was significantly lower in the food-deprived than in the refed rats (P < 0.05) but was unaffected by exercise. Exercised 24-h refed rats had significantly elevated muscle GSSG concentration compared with rested rats, along with a higher GSH peroxidase and a lower gamma-glutamyltranspeptidase activity (P < 0.05). These data indicate that both food deprivation-refeeding and exhaustive exercise influence liver and skeletal muscle glutathione status and that these changes may be controlled by hepatic glutathione synthesis and release due to hormonal stimulation.
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PMID:Alteration of glutathione and antioxidant status with exercise in unfed and refed rats. 868 45