Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the recently advanced hypothesis that glutathione [L-gamma-glutamyl-L-cysteinyl glycine (GSH)] regulates deiodinating enzyme activities, accounting for the decreased conversion of T4 to T3 in the liver of fetal and starved animals, we investigated thyroid hormone metabolism in GSH-depleted neoplastic and normal hepatocytes. In monkey hepatocarcinoma cells, intracellular total GSH decreased below 10% of the control value (approximately 25 micrograms/mg protein) when cells were grown for 44 h in medium deficient in cystine and methionine or in cystine alone. The latter finding indicated that transsulfuration from methionine to cysteine was defective in these neoplastic cells. In primary cultured adult rat hepatocytes, on the other hand, the transsulfuration pathway was intact, and total GSH decreased below 10% of control (approximately 20 micrograms/mg protein) only in cells grown in cystine- and methionine-deficient medium. In both cell types, the oxidized GSH fraction remained constant (2-5% of total). Incubation with 125I-labeled T4 and T3, followed by chromatography, was used to evaluate 5-deiodination in hepatocarcinoma cells and both 5- and 5'-deiodination in normal hepatocytes. Deiodination was not decreased by GSH deficiency in either case, but was actually increased in hepatocarcinoma cells. This resulted from an increase in the Vmax of 5-deiodinase related to growth arrest. Diamide at 2 mM reversibly inhibited both 5'- and 5'-deiodination in rat hepatocytes, accompanied by decreased total GSH as well as increased GSH disulfide (27% of total). The data suggest that GSH is so abundant in the liver that hepatocytes can tolerate a greater than 90% decrease in intracellular concentration without any change in thyroid hormone deiodination and indicate that altered thyroid hormone metabolism in the fetus and in starvation cannot be accounted for by a decreased hepatic GSH concentration.
 ...
PMID:Glutathione deficiency induced by cystine and/or methionine deprivation does not affect thyroid hormone deiodination in cultured rat hepatocytes and monkey hepatocarcinoma cells. 679 Feb 65

The specific binding of [125I]T3 and [125I]rT3 to nuclear extracts of rat and pork liver was studied. The Ka values of the binding of T3 and rT3 to nuclear extracts were similar (0.65 +/- 0.12 vs. 0.68 +/- 0.10 x 10(9) M-1; P = NS), but the maximal binding capacity for T3 was smaller than that for rT3 (333 +/- 36 vs. 1209 +/- 338 fmol/mg DNA; P less than 0.05). The amount of nonradioactive T4 required to cause a 50% displacement of [125I]T3 from the nuclear binding sites was, on a molar basis, 27 times greater than that of T3 in the case of pork liver and 110 times greater than that of T3 in the case of rat liver. Similarly, rT3-binding sites were highly specific. Relative to rT3, 16- and a 100-fold greater molar excesses of T4 were required to cause a 50% displacement of [125I[rT3 from the nuclear binding sites in pork and rat liver, respectively. Similarly, 700--2150 times more rT3 than T3 was required to obtain a 50% displacement of [125I]T3; in contrast, 50--250 times more T3 than rT3 was needed to displace 50% specifically bound [125I]rT3. Reduced glutathione and other sulfhydryl (SH)-reducing agents increased, whereas oxidized glutathione and SH-oxidizing or -binding agents decreased the binding of [125I]T3 and [125I]rT3 to nuclear extracts, with one exception. Dithiothreitol, a potent SH-reducing agent, reduced the binding of rT3 whereas it increased the binding of T3 to the nuclear binding sites. A 48-h fast was associated with a significant reduction in the maximal binding capacity of nuclear extracts for T3 (control vs. fasting rats, 589 +/- 92 vs. 339 +/- 50 fmol T3/mg DNA; P less than 0.05) and rT3 (1620 +/- 162 vs. 693 +/- 102 fmol rT3/mg DNA; P less than 0.005) without changes in affinity. The data suggest that 1) there exist specific high affinity, low capacity nuclear rT3-binding sites in rat and pork liver which are distinct from the nuclear T3 receptors, and 2) rT3- and T3-binding sites are reduced in parallel during starvation.
 ...
PMID:Specific nuclear binding sites of triiodothyronine and reverse triiodothyronine in rat and pork liver: similarities and discrepancies. 707 48

Starving rats for 24 hours causes the GSH values of the liver to fall by about 2.0 mumol/g of liver and the mixed disulphide values to rise by about the same amount. Total glutathione remains unchanged. Readily permeable organic copper complexes with superoxide-dismutating properties are capable of partially reversing these starvation-induced changes. 5 minutes after intraportal administration of 1.6 micrograms of Cu succinate per 260 g of rat, the GSH value of starved animals has risen from 5.12 mumols/g of liver to 5.94 mumols, and the mixed disulphide value has fallen from 3.64 mumols of GSH equivalents/g of liver to 2.75 mumols. 1.6 micrograms of Cu indomethacine administered by the same route cause a subsequent rise in GSH of 0.83 mumol/g of liver and a drop in the mixed disulphide value of 0.80 mumol of GSH equivalents. Cu salicylate and Cu aspirinate exhibit somewhat milder effects of the same type. In contrast, Cu tyrosine causes a slight drop in GSH in starved animals. None of these treatments have any effect on the glutathione parameters in animals which have been fed. It is proposed that a starvation-induced increase in the stationary O(2) equilibrium concentration probably occurs. Superoxide radicals shift the redox status of glutathione in the direction of the disulphides. This situation can be partly reversed by intraportal administration of organic copper complexes.U
 ...
PMID:The effect of organic copper complexes on the glutathione status of the liver of fed and rats starved for 24 hours. 713 27

Starvation causes several changes in the various processes of biotransformation. The focus of this review is on biotransformation of various aromatic and other compounds whose metabolism is catalyzed in phase I by isozymes belonging to the CYP2E1 gene subfamily, while in phase II phenol-UDPGT or conjugation with GSH play a dominant role. The other ways of conjugation are beyond the scope of this review. The reason why this aspect has been chosen is that the capacity of these reactions is profoundly altered by nutritional conditions. There is a balance between the two phases of biotransformation. Therefore, under standard circumstances in a well-fed state the intermediate formed in the course of phase I is converted to a conjugated compound rapidly, as a result of phase II. However, in starvation the pattern of drug metabolism is altered and the balance between the two phases is changed. This alteration of drug metabolism upon starvation is partly connected to the changes of cofactor supplies due to the metabolic state.
 ...
PMID:Increased oxidation and decreased conjugation of drugs in the liver caused by starvation. Altered metabolism of certain aromatic compounds and acetone. 772 9

Glutathione (GSH) contributes to the detoxification of anticancer drugs through the operation of specific glutathione S-transferases (GST) and innate, or acquired, overexpression of this enzyme family has been frequently observed in tumor cell lines. In the GMA32 line of Chinese hamster fibroblasts, we showed that GSH starvation produced by exposing cells to buthionine sulfoximine (BSO) increased the toxicity of chlorambucil and melphalan, but not that of N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), cisplatine and doxorubicin. This indicates that efficient mechanisms of detoxification using GSH operate for chlorambucil and melphalan, but not for the other drugs in these cells. We then showed that GSH depletion could be selectively and transiently induced in the mu GST overexpressing cell line derived from GMA32, HC474, by exposing cells to substrates specific to the overexpressed isozyme. Exposing cells to such a substrate, trans-stilbene oxide, does not alter the sensibility of GMA32 cells to melphalan and chlorambucil, but increases that of HC474 cells to these drugs, to an extent comparable to that obtained with BSO. This observation highlights the possibility of exploiting GST overexpression, a frequent feature of tumor cells, to selectively sensitize these undesirable cells to anticancer drugs.
 ...
PMID:A glutathione depletion selectively imposed on mu glutathione S-transferase overproducing cells increases nitrogen mustard toxicity. 785 20

The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.
 ...
PMID:Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis. 802 75

We have investigated the effect of extracellular ATP on tumour-cell proliferation and GSH levels in Ehrlich-ascites-tumour-bearing mice. After daily administration of exogenous ATP (1 mmol/kg) during 7 days, we found a 56% inhibition of tumour growth, precisely when controls show the highest rates of cell proliferation and the highest levels of GSH. This effect is accompanied by a decrease in GSH content in the tumour, but not in normal tissues. The decrease in GSH concentration within the cancer cells is associated with a decrease in gamma-glutamylcysteine synthetase activity and in protein synthesis. Growth inhibition is mediated by generation of extracellular adenosine, which subsequently increases intracellular levels of ATP and decreases intracellular levels of UTP in the cancer cells. Our results suggest that inhibition of tumour growth by ATP is due to an adenosine-dependent pyrimidine starvation effect.
 ...
PMID:Inhibition of cancer growth and selective glutathione depletion in Ehrlich tumour cells in vivo by extracellular ATP. 812 37

The level of malondialdehyde (MDA), an index of lipid peroxidation, and the antioxidants superoxide dismutase (SOD) and glutathione (GSH), as well as the activity of Na+, K(+)-ATPase, were assessed in whole rat brain after immobilization, anemic hypoxia (NaNO2) and 72 h starvation. The effect of these stressors on plasma glucose and corticosterone levels was also observed. Hypoxia and starvation stimulated the lipid peroxide formation in brain as indicated by an increase in the level of MDA, being higher after starvation than hypoxia. Brain SOD activity was also increased in response to hypoxia and starvation while GSH content was only diminished in hypoxia. However, neither MDA nor antioxidants were affected by immobilization. On the other hand, the activity of brain Na+, K(+)-ATPase was significantly increased by immobilization and hypoxia but decreased in starvation. A similar pattern of change was also observed in plasma glucose and corticosterone levels in response to these stressors. These results elucidate differences in the biochemical response of animals towards various types of stress, with increased lipid peroxide formation in hypoxia and starvation.
 ...
PMID:Effect of various stressors on the level of lipid peroxide, antioxidants and Na+, K(+)-ATPase activity in rat brain. 862 Sep 36

When the yeast Saccharomyces cerevisiae sigma 1278b was starved for nitrogen, the total glutathione (GSH) pool increased from 7 to 17 nmol (mg dry wt)-1 during the first 2 h and then declined. More than 90% of the total GSH shifted towards the central vacuole during this time. This transient stimulation was not observed in the presence of buthionine-(S,R)-sulphoximine (BSO), a specific transition-state-analogue inhibitor of gamma-glutamylcysteine synthase (gamma-GCS), nor in a mutant strain deficient in this enzyme- gamma-Glutamyltranspeptidase (gamma-GT), a vacuolar enzyme responsible for the initial step of GSH degradation, was derepressed during nitrogen starvation. This mechanism can apparently enable the starved yeast cell to use the constituent amino acids from GSH which accumulate in the vacuole to satisfy its growth requirements for nitrogen.
 ...
PMID:An important role for glutathione and gamma-glutamyltranspeptidase in the supply of growth requirements during nitrogen starvation of the yeast Saccharomyces cerevisiae. 920 64

We studied the effect of prostaglandin F2 alpha on parameters related to microsomal metabolism (free radical production and lipid peroxidation, glutathione content and activity of microsomal oxidases) after an induction by ethanol or acetone combined with starvation. Long-term ethanol administration led to a significant increase in lipid peroxide formation and NADPH-dependent chemiluminescence amplified by luminol and lucigenin. At the same time hydrogen peroxide production and NADPH-stimulated lipid peroxidation were enhanced although the effect did not reach the level of statistical significance. The concentration of reduced glutathione (GSH) in the liver was decreased 2-fold, whereas oxidized glutathione (GSSG) content remained unaltered. Ethanol intoxication resulted in an increase in 7-ethoxycoumarin-O-deethylase (ECOD), 7-benzyloxycoumarin-O-deethylase (BCOD) and 7-ethoxy-resorufin-O-deethylase (EROD) activities, whereas 7-pentoxyresorufin-O-deethylase (PROD) and ethylmorphin-N-demethylase (EMND) activities were unaltered. The combination of acetone treatment with starvation resulted in a significant increase in lipid and hydrogen peroxide formation, NADPH-dependent lipid peroxidation and chemiluminescence. GSH and GSSG concentration in the liver dramatically decreased 5- and 3-fold, respectively. The acetone treatment led to significant increase in EROD, ECOD, BCOD, PROD and EMND activities. The treatment of ethanol-intoxicated rats with prostaglandin F2 alpha (PGF2 alpha) exerted more pronounced prooxidant effect on liver than action of alcohol itself. At the same time, PGF2 alpha improved most of parameters changed by acetone treatment combined with starvation, decreasing lipid peroxide and radical formation and enhancing GSH and GSSG contents.
 ...
PMID:Effect of prostaglandin F2 alpha on free radical generation, glutathione content and microsomal oxidase activities in rat liver microsomes induced either by ethanol or acetone. 956 47


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>