Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methotrexate is glutamylated in cultured hepatoma cells to derivatives that contain a total of 2 to 5 gamma-glutamyl residues. The rate of polyglutamate formation and extent of accumulation are saturable with respect to both medium concentration of methotrexate and time. Maximal rates of glutamylation and accumulation of methotrexate polyglutamates at steady state occur at approximately 10 microM extracellular methotrexate. Inclusion of physiologic concentrations of insulin or removal of folate from the medium each cause a doubling of the rate of glutamylation, and these effects are additive. Insulin and folate restriction also enhance the accumulation of methotrexate polyglutamates. In combination they result in a doubling in the intracellular methotrexate polyglutamate pool at steady state and a shift in the polyglutamate distribution to longer-chain-length species. The importance of the longer-chain-length polyglutamates is apparent from the 6-hr retention of the polyglutamate species: Glu2, 15%; Glu3, 21%; Glu4, 50%; and Glu5, 83%. In probing the glutamylation reaction, a new series of inhibitors have been initiated. These are based upon replacing the incoming glutamate with 4-fluoroglutamate or synthesizing methotrexate with the glutamate replaced by 4-fluoroglutamate. The 4-fluoroglutamyl analogs of methotrexate are effective inhibitors of dihydrofolate reductase but cannot be glutamylated. They will be utilized to probe the role of glutamylation in antifolate activity and folate metabolism.
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PMID:Glutamylation of methotrexate in hepatoma cells in vitro: regulation and the development of specific inhibitors. 241 93

Glutamine synthetase and glutaminase activities in a series of hepatoma cells of human and rat origins were determined for comparison with normal liver tissues. Marked decrease in glutamine synthetase activity was observed in the tumor cells. Phosphate-dependent and phosphate-independent glutaminase activities were increased compared with those from normal liver tissues. Well coupled mitochondria were isolated from HuH 13 line of human hepatoma cells and human liver. Oxypolarographic tests showed that glutamine oxidation was prominent in the tumor mitochondria, while mitochondria from the liver showed a feeble glutamine oxidation. Glutamine oxidation was inhibited by prior incubation of the mitochondria with DON (6-diazo-5-oxo-L-norleucine), which inhibited mitochondrial glutaminase. These results indicate that the product of glutamine hydrolysis, glutamate, is catabolized in the tumor mitochondria to supply ATP.
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PMID:Glutamine synthetase and glutaminase activities in various hepatoma cells. 257 54

Glutamate dehydrogenase (GDH) was purified to homogeneity from cerebellar tissue of three normal subjects and seven patients with four distinct types of degenerative neurological disorders. Nonequilibrium pH gradient gel electrophoresis showed that the purified enzyme consists of four major isoproteins designated GDH 1, 2, 3, and 4. With one exception, the relative abundance and isoelectric points of the GDH isoproteins decrease and the molecular weights increase progressively going from isoprotein 1 to isoprotein 4. The enzyme isolated from the brain of one patient with a variant form of multiple system atrophy displayed marked reduction of GDH isoprotein 1. The Km values of the patients' GDH for alpha-ketoglutarate, glutamate, NADH, and NADPH were significantly increased as compared to GDH obtained from normal and neurologic control subjects. In addition, glutamate levels were reduced markedly in the patient's cerebellum. Pulse-chase studies have shown that both the human hepatoma HepG2 and the human glioma U373 cell lines synthesize exclusively GDH isoprotein 2. The different GDH isoproteins do not have a precursor-product relationship and may represent products of different GDH mRNA species.
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PMID:Characterization of glutamate dehydrogenase isoproteins purified from the cerebellum of normal subjects and patients with degenerative neurological disorders, and from human neoplastic cell lines. 257 5

A methotrexate (MTX) analog containing fluorine at the gamma-carbon of the glutamate moiety, gamma-fluoromethotrexate (FMTX), has been synthesized and evaluated for its biochemical and pharmacological properties. FMTX inhibition of dihydrofolate reductase from several sources is nearly equivalent to that shown by MTX. Most important, FMTX is an exceedingly poor substrate for folylpoly (gamma-glutamate) synthetase, the enzyme that catalyzes the biosynthesis of the highly-retained, cytotoxic MTX polyglutamates. Uptake experiments in H35 hepatoma cells show that FMTX accumulates to approximately the same extent as MTX at steady state. The rapid efflux of both derivatives is also very similar. The major difference detected in cells between the two compounds is the meager glutamylation of FMTX, due to the electronegative properties of the fluorine adjacent to the potential amide-forming carboxyl group. Exposure of dividing cells to 50 microM MTX for 2 and 6 hr results in the formation of 55 and 130 nmol, respectively, of the polyglutamates (more than two glutamate residues)/g of cell protein. With FMTX these values were reduced by 98% and 93%, respectively. Growth inhibition studies show that MTX is only 12-fold more toxic than FMTX when the cells are exposed to each derivative continuously for 72 hr. When the exposure time is reduced, a greater disparity between the inhibitory effects is observed; with a 2-hr pulse, MTX is 2300-fold more effective than FMTX. These data correlate with the effects of pulses of FMTX and MIX on de novo thymidylate biosynthesis in intact cells. The results indicate that of the parameters examined, the vastly reduced toxicity of FMTX after its removal from the culture medium is best correlated with impaired glutamylation. The data strongly suggest that prolonged toxicity of MTX is a result of metabolic conversion to MTX polyglutamates and that these effects are far more dramatic in short-term than in long-term exposure to the antifolates.
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PMID:gamma-Fluoromethotrexate: synthesis and biological activity of a potent inhibitor of dihydrofolate reductase with greatly diminished ability to form poly-gamma-glutamates. 258 Dec 52

Growth of a highly-deviated ascites hepatoma (Yoshida AH-130) in rats caused initial hyperplastic enlargement of the liver, followed by progressive reduction to a size lower than that seen in controls. The time-course of this biphasic change in liver weight roughly corresponded to the exponential and stationary phases of tumour growth. Histologically, scattered small foci of perilobular necrosis were observed during the hyperplastic phase and these were consistently associated with a moderate elevation of glutamate-pyruvate transaminase (GPT) activity in the blood plasma. By contrast, signs of necrosis were absent and plasma GTP levels had returned to normal during the phase of hepatic involution, which was characterized by enhanced apoptosis, a type of single-cell death known to be involved in the regulation of tissue size under both normal and pathological conditions. Biochemically, alterations in liver protein mass resulted from changed rates of tissue protein degradation. The apoptotic bodies could either be lost from the liver via blood, lymph and bile, or phagocytosed and degraded by adjacent cells. Disposal of the apoptotic bodies is likely to account, at least in part, for the enhanced rates of liver protein turnover that characterize hepatic involution.
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PMID:Regulation of cell turnover in the livers of tumour-bearing rats: occurrence of apoptosis. 279 40

Well coupled mitochondria were isolated from transplantable chicken hepatoma induced by MC-29 virus. The mitochondrial phosphate-dependent and phosphate-independent glutaminase activities were increased compared with those from normal chicken liver. Glutamate dehydrogenase was undetectable in the tumor mitochondria. Oxypolarographic tests showed the following: glutamine oxidation was prominent in the tumor mitochondria and was mediated through an NAD-linked reaction, while mitochondria from the liver showed a feeble glutamine oxidation; glutamine oxidation by tumor mitochondria was inhibited either by aminooxyacetate, inhibitor of transaminases, or prior incubation of mitochondria with DON (6-diazo-5-oxonorleucine), which inhibited mitochondrial glutaminases. Bromofuroate, inhibitor of glutamate dehydrogenase, had little or no effect; and glutamate oxidation was also inhibited by aminooxyacetate, while it was not affected by DON. These findings clearly show a high glutamate oxidation activity in the hepatoma and indicate that the product of glutamine hydrolysis, glutamate, is catabolized via transamination in the mitochondria to supply ATP.
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PMID:Prominent glutamine oxidation activity in mitochondria of avian transplantable hepatoma induced by MC-29 virus. 301 1

The transport of glycine and L-lysine into murine P388 leukemia cells has been examined. Glycine transport appears to be shared by both systems A and ASC in P388 cells. Glycine transport is Na+-dependent and is effectively blocked by alpha-(methylamino)isobutyric acid, threonine and alanine but only a marginal reduction in transport is seen with 100-fold excess cold 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid. System gly is not expressed in P388 cells. Lysine is largely transported by a Na+-independent, pH-insensitive system with a Km of 0.079 mM. Lysine transport is relatively unaffected by the addition of 100-fold excess cold alpha-(methylamino)isobutyric acid, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid and the anionic amino acids, L-glutamate and L-aspartate. A partial inhibition of lysine transport was observed with L-threonine and L-leucine while L-arginine and L-histidine radically decreased lysine transport. Lysine appears to be transported by a system similar to the system y+ seen in cultured human fibroblasts, Ehrlich ascites cells, and hepatoma cell lines.
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PMID:Further studies on amino acid transport in murine P388 leukemia cells in vitro. Presence of system y+. 310 85

1. The occurrence and characterization of acidic amino acid transport in the plasma membrane of a variety of cells and tissues of a number of organisms is reviewed. 2. Several cell types, especially in brain, possess both high- and low-affinity transport systems for acidic amino acids. 3. High-affinity systems in brain may function to remove neurotransmitter amino acid from the extracellular environment. 4. Many cell systems for acidic amino acid transport are energized by an inwardly directed Na+ gradient. Moreover, certain cell types, such as rat brain neurons, human placental trophoblast and rabbit and rat kidney cortex epithelium, respond to an outwardly directed K+ gradient as an additional source of energization. This simultaneous action may account for the high accumulation ratios seen with acidic amino acids. 5. Rabbit kidney has been found to have a glutamate-H+ co-transport system which is subject to stimulation by protons in the medium. 6. Acidic amino acid transport in rat brain neurons occurs with a stoichiometric coupling of 1 mol of amino acid to 2 mol of Na+. For rabbit intestine, one Na+ is predicted to migrate for each mol of amino acid. 7. Uptake in rat kidney cortex and in high-K+ dog erythrocytes is electrogenic. However, uptake in rabbit and newt kidney and in rat and rabbit intestine is electroneutral. 8. Na+-independent acidic amino acid transport systems have been described in the mouse lymphocyte, the human fibroblast, the mouse Ehrlich cell and in rat hepatoma cells. 9. In a number of cell systems, D-acidic amino acids have substantial affinity for transport; D-glutamate, in a number of systems, however, appears to have little reactivity. 10. Acidic amino acid transport in some cell systems appears to occur via the "classical" routes (Christensen, Adv. Enzymol. Relat. Areas Mol. Biol. 49, 41-101, 1979). For example, uptake in the Ehrlich cell is partitioned between the Na+-dependent A system (which transports a wide spectrum of neutral amino acids), the Na+-dependent ASC system (which transports alanine, serine, threonine, homoserine, etc.), and the Na+-independent L system (which shows reactivity centering around neutral amino acids such as leucine and phenylalanine). Also, a minor component of uptake in mouse lymphocytes occurs by a route resembling the A system. 11. Human fibroblasts possess a Na+-independent adaptive transport system for cystine and glutamate that is enhanced in activity by cystine starvation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Acidic amino acid transport in animal cells and tissues. 330 25

The amount of reduced glutathione in transplantable hepatomas and in a primary DEN-induced hepatoma is lower than in normal liver. In all tumors examined, the glutathione decrease is not due to an increase of oxidized glutathione. In this paper the in vitro activities of two enzymes involved in glutathione synthesis, gamma-glutamylcysteine synthetase and glutathione synthetase, are studied in normal adult rat liver, in regenerating rat liver and in highly anaplastic Yoshida AH-130 hepatoma cells. The activity of these enzymes was determined in the postmicrosomal supernatant fraction as nmoles of [U-14C]-glutamate incorporated into product per mg of soluble protein. In Yoshida AH-130 hepatoma, the gamma-glutamylcysteine synthetase and glutathione synthetase activities are lower in respect to normal liver. This is in agreement with the low glutathione content observed in the hepatoma cells. On the other hand, in regenerating liver, there are minimal differences in comparison with normal liver.
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PMID:Glutathione synthesis in normal liver and in Yoshida AH-130 hepatoma. 380 95

Nineteen enzymes showing highest activity in liver were examined in human and rodent tissues and cultured cells using starch-gel electrophoresis. The rat hepatoma line Faza 967 strongly expressed 13 of these enzymes. A series of somatic cell hybrids, constructed between Faza and cells of non-hepatic origin derived from man or from Chinese hamster, were examined for expression of these enzymes. Some of the human/rat hybrids continued to produce rat liver-specific enzymes, and the human forms of the enzymes glutamate-pyruvate transaminase, alpha-glycerophosphate dehydrogenase, alcohol dehydrogenase and pyruvate kinase L were reexpressed in a few cases.
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PMID:Regulation of expression of liver-specific enzymes. I. Detection in mammalian tissues and cultured cells. 612 89


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