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)

In previous studies, we observed decreased uptake of 14C-labeled L-aspartate and L-glutamate in s.c. transplants of several rapidly growing hepatomas relative to that in normal liver. The present report extends these observations to isolated cells and indicates that circulation differences cannot be the major factor. Mean net uptakes for the two dicarboxylic amino acids in cells from the rapidly growing Morris Hepatomas 7288ctc and 7777 were 5 to 26% of corresponding values for normal hepatocytes. Rates for net uptake in Hepatoma 7787 cells were intermediate between those of the rapidly growing hepatomas and hepatocytes, while the rates for Hepatoma 5123C cells and hepatocytes were similar. The contribution of sodium-dependent uptake to the mean total net uptake of [14C]aspartate and [14C]glutamate tended to be higher in hepatoma cells than in hepatocytes. Studies with isolated hepatocytes and Hepatoma 5123C cells showed no significant effect on uptake by 10 mM alpha-(methylamino)isobutyric acid and 10 mM 2-amino-2-carboxybicyclo[2.2.1]heptane. On the other hand, L-cysteic acid, L-alanosine, and N-phosphonacetyl-L-aspartic acid were shown to be effective inhibitors of sodium-dependent uptake in Hepatoma 5123C cells. The data suggest that the A and L systems are not major contributors to the uptake of dicarboxylic amino acids in hepatic cells. It was concluded that decreased uptake of dicarboxylic amino acids in rapidly growing hepatomas may accompany decreased metabolism of these dietary nonessential amino acids.
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PMID:Uptake of 14C-labeled dicarboxylic amino acids in hepatocytes and hepatoma cells. 724 63

In contrast to the increased uptake of amino acids which has been found in many neoplastic cells, we have observed a decrease in the net uptake of [14C]aspartate and [14C]glutamate in rapidly growing hepatomas relative to rat host liver. When measured 10 min after s.c. injection, the radioactivity from 14C-labeled dicarboxylic amino acids was greater in liver than in all other tissues examined (blood, skeletal, muscle, heart, spleen, lung, and brain) except kidney, where there was an approximately 2-fold greater uptake of aspartate and 10-fold greater uptake of glutamate. Mean uptakes in the rapidly growing Morris hepatomas 7288CTC and 7777 were 19 to 26% of corresponding values for the host livers. Comparison with uptake of 3H2O indicated that these low values were not solely due to differences in circulation. Decreased uptake was not accompanied by equivalent decreases in the concentration of aspartate and glutamate in the tumors. There were small changes in the net uptake of these amino acids in the slowly growing hepatoma 7787 and no significant differences in regenerating liver and hepatoma 5123C, a tumor of intermediate growth rate. The net uptake of [14C]arginine and [14C]lysine in the hepatomas was similar to that in host livers, except for a 250% increase in uptake of [14C]lysine in hepatoma 5123C. A decreased uptake of the magnitude seen with dicarboxylic amino acids in rapidly growing hepatomas has not been observed with other amino acids.
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PMID:Decreased uptake of 14C-labeled dicarboxylic amino acids in rapidly growing hepatomas. 747 Oct 51

Folates and antifolates are converted to polyglutamates, which are better retained in cells and may also bind more tightly to cellular proteins than the parent compounds. The regulation of the process of polyglutamate formation and breakdown is not fully clarified yet and is being studied by a number of approaches. An early observation concerning the potential regulation of polyglutamate formation was that insulin caused a marked increase in the rate and accumulation of polyglutamates of methotrexate (MTX) in rat hepatoma cells. The present study demonstrated that insulin caused a decrease in the activity of gamma-glutamyl hydrolase (GH), the enzyme that degrades polyglutamates, that was inversely commensurate with the increase in the synthesis of MTX polyglutamates. The effects of insulin on GH activity with regard to concentration, time of onset, and the effect of N6, O2' dibutyryl cAMP and theophylline were consistent with the reduction in GH being responsible for the increase in cellular MTX polyglutamate accumulation. Insulin addition also led to an increase in folate polyglutamates. The insulin effects were also seen with H35D cells, a subline with enhanced glutamyl hydrolase activity as a result of having been made resistant to 5, 10-dideazatetrahydrofolic acid. When H35 cells with insulin were compared with H35D cells lacking insulin, there was an 8-fold increase in GH and a 44-fold decrease in the number of gamma-glutamate residues added to MTX.
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PMID:Insulin-dependent suppression in glutamyl hydrolase activity and elevated cellular methotrexate polyglutamates. 750 69

gamma-Glutamyl hydrolase is a ubiquitous enzyme that has the capacity to cleave gamma-glutamyl bonds of cellular folyl- and antifolylpoly-gamma-glutamates. This study has revealed that the enzyme is secreted by primary cultures of rat hepatocytes and by H35 hepatoma cells. It was found that more than 99% of the total enzyme from H35 cells accumulated in the medium after 48 hr incubation with the serum-free medium. The cells were shown to remain intact during the secretion period since lactate dehydrogenase, dihydrofolate reductase and lysosomal hydrolases other than gamma-glutamyl hydrolase were retained within the cell. When PteGlu5 (folylGlu4) is used as a substrate the initial product is PteGlu (folate), and there is no appearance of intermediate chain length pteroyl polyglutamates. Therefore, the secreted and cellular gamma-glutamyl hydrolase from hepatoma cells appears to be an endopeptidase. Polyclonal antibodies to the poly-gamma-glutamate substrates of the enzyme were prepared and characterized. The antibodies recognize the structural differences between alpha- and gamma-glutamyl linkages but appear equally active with PteGlu5 and its analogs such as 4-NH2-10-CH3PteGlu5 and pABAGlu5. The affinity of the antibodies is related to the gamma-glutamyl structure since L-glutamic acid, folate or p-aminobenzoic acid are inactive with the antibodies. Furthermore, poly-gamma-glutamate has lower affinity for the antibodies than the poly-gamma-glutamate derivatives of PteGlu, 4-NH2-10-CH3PteGlu or pABA.
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PMID:The properties and function of gamma-glutamyl hydrolase and poly-gamma-glutamate. 768 89

H4IIEC3 (H4), a differentiated rat hepatoma line and H5, its dedifferentiated subclone, were investigated as proliferating spheroids and as implanted subcutaneous tumors in juvenile rats. H4 cells formed tight, round spheroids whereas H5 cells formed loose, grape-like structures. 31P MR spectra showed that phosphocreatine was present in H5 spheroids but not in H4 spheroids or tumors. [13C]Lactate production from [13C]glucose, with no detectable uptake of [13C]alanine, indicated that energy production in H5 spheroids was primarily via glycolysis. No [13C]glucose utilization was detected in H4 spheroids, but uptake of alanine and accumulation of labeled lactate, glutamate and glutamine indicated oxidation via the tricarboxylic acid (TCA) cycle. Tumors of H4 cells were well perfused, unlike tumors of H5 cells which were highly necrotic. Following i.v. infusion with [13C]alanine, [13C]lactate and glutamate, evidence of oxidation via the TCA cycle, were observed in H4 tumors. Thus the results obtained by 31P and 13C MRS correlated with the differentiation state of H4 and H5 spheroids and tumors.
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PMID:Comparative NMR study of a differentiated rat hepatoma and its dedifferentiated subclone cultured as spheroids and as implanted tumors. 784 Oct 24

This research demonstrates how the chemical reaction interface mass spectrometry (CRIMS) approach works for a study of amino acid metabolism in cell culture. 15N-selective chromatograms from both the culture medium and the cytosol of human hepatoma Hep G2 cells that were incubated in the presence of either 12 mM (alpha-15N)glutamine or (alpha-15N)asparagine have been produced. The time course of the distribution of 15N among different amino acids, as well as the enrichment for each amino acid, were observed over a 144 h period. Labeled glutamine was quickly converted into glutamate. After 144 h of incubation, the total amount of 15N was distributed primarily among alanine (50%), proline (28%) and glutamate (21%). The 15N enrichment of alanine and proline reached 44% and 41% respectively. Asparagine was only slowly metabolized by the cells. In addition to the 82% that was retained in asparagine, the remaining 15N in the media at 144 h was found primarily in alanine (8%), glutamate (6.8%) and proline (2.2%). Their enrichments were 20%, 36% and 19% respectively. The minimum detectable amount was 17 pg of 15N entering the CRI. CRIMS appears to be a powerful, facile approach for 15N-tracer experiments.
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PMID:Tracing 15N with chemical reaction interface mass spectrometry: a demonstration using 15N-labeled glutamine and asparagine substrates in cell culture. 784 Dec 9

gamma-Glutamyl hydrolase has been partially purified and characterized from conditioned culture medium of H35 hepatoma cells. Evidence for heterogeneity of the enzyme is derived from its elution as three distinct peaks of enzymatic activity when the enzyme is purified by TSK-butyl-Sepharose column chromatography. These three enzyme fractions appear to have identical catalytic properties but, as yet, the basis for their resolution is not understood. A rapid, sensitive and simple assay based on reverse-phase HPLC fluorescent detection with pre-column derivatization using o-phthalaldehyde (OPA) was developed to separate OPA-derivatives of poly-gamma-glutamates and glutamic acid. Using this assay and the standard HPLC assay for pteroylpolyglutamates, the enzyme appears to be an endopeptidase with respect to pteroylpenta-gamma-glutamate (PteGlu5), methotrexate penta-gamma-glutamate (4-NH2-10-CH3PteGlu5) and p-aminobenzoyl-penta-gamma-glutamate (pABAGlu5). The initial products are PteGlu1 (or 4-NH2-10-CH3PteGlu1 or pABAGlu1) and intact tetra-gamma-glutamate, which is subsequently degraded to glutamic acid. When penta-gamma-glutamate is the substrate, the cleavage of the gamma-bonds by the enzyme is less ordered, with the early appearance of mono-, di-, tri- and tetraglutamate. Poly-alpha-glutamate is not a substrate nor are pABA-gamma-Glu5 or penta-gamma-glutamate covalently linked to albumin. 4-NH2-10-CH3PteGlu2 or Glu5 bound to dihydrofolate reductase is not a substrate for the enzyme, offering further evidence that protein-associated poly-gamma-glutamates are poor substrates for gamma-glutamyl hydrolase from H35 hepatoma cells.
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PMID:The properties of the secreted gamma-glutamyl hydrolases from H35 hepatoma cells. 834 22

A recent study from our laboratory demonstrated that cyclosporine (CsA), a prototype immunosuppressant, enhanced the growth of carcinogen-induced enzyme altered foci in rat liver, suggesting that CsA may stimulate development of hepatocellular carcinomas. In the present study, we examined (i) whether CsA accelerates development of hepatocellular carcinomas in experimental animals, (ii) whether CsA stimulates the proliferation of resting hepatocyte in vivo and (iii) whether CsA modulates the production of growth factors implicated in liver cell growth, hepatocyte growth factor (HGF), transforming growth factor alpha (TGF alpha) and transforming growth factor beta 1 (TGF beta 1). Foci of hepatocytes, positive for glutathione S-transferase placental form were induced in male F344 rats by a single dose of diethylnitrosamine followed by 7 weeks promotion by a choline-deficient diet. The animals were then divided in two groups, and subsequent development of hepatocellular carcinomas was compared in rats fed a basal diet or a basal diet containing 0.015% CsA. Development of hepatocellular carcinoma was accelerated in the rats maintained on a CsA diet. Feeding a CsA diet as the sole treatment, for 2, 4 and 10 weeks induced significant increases in liver weight, and resulted also in an enhanced incorporation by hepatocytes of 5-bromo-2-deoxy-uridine. Serum levels of glutamate-oxaloacetate transferase, glutamate-pyruvate transferase and lactic dehydrogenase were not altered by feeding a CsA diet. Northern Blot analyses of the expression of HGF, TGF alpha and TGF beta 1 mRNAs in the liver showed similar patterns of expression between rats fed a basal diet and a CsA diet. The levels of HGF mRNA were not altered in the lungs and kidneys of rats fed a CsA diet. These results indicate that CsA stimulates rat liver cell proliferation in vivo without inducing liver cell necrosis, and that this effect may contribute to accelerated development of hepatocellular carcinomas in rats fed a CsA diet. As previously observed with BR 931, a hypolipidemic peroxisome proliferator, stimulation of liver cell growth by CsA did not entail changes in the production of HGF, TGF alpha or TGF beta 1.
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PMID:Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats. 835 42

This paper presents the first complete purification of the branched chain aminotransferase (EC 2.6.1.42) from rat brain cytosol (BCATc). On sodium dodecyl sulfate-polyacrylamide gel electrophoresis the enzyme appeared as a single band with a molecular mass of 47 kDa; however, gel exclusion chromatography suggested that BCATc is a dimer. Comparison of tryptic peptide maps of BCATc and the mitochondrial form of the enzyme (BCATm) indicated that they are different proteins. Experiments with protein labeling reagents, in particular sulfhydryl reagents, also suggested that there may be some distinct structural differences in BCATc and BCATm. Nevertheless, BCATc and BCATm showed similar specificities for amino acid and alpha-keto acid substrates. Both enzymes transaminated branched chain amino acids, their straight chain analogs, L-alloisoleucine and glutamate. A broader range of alpha-keto acids than amino acids was accepted as substrate including alpha-ketobutyrate and the alpha-keto acid of methionine. Both enzymes exhibited ping-pong kinetics with apparent Km values for leucine and isoleucine of about 1 and 5 mM for valine, respectively. Km values for alpha-ketoglutarate ranged from about 0.6 to 3 mM depending on the amino acid substrate. Polyclonal antibodies were raised in rabbits against purified BCATc. BCATc antiserum neutralized branched chain aminotransferase activity in rat brain cytosol but did not affect the activity in a heart mitochondrial extract. However, immunoblotting showed that BCATc and BCATm do share common epitopes since BCATm antiserum recognized BCATc on the immunoblots. The tissue distribution of BCATc was examined using BCATc and BCATm antisera. These data showed that BCATc was found in adult and fetal rat brain, cultured cells from fetal rat brain cortex, ovary, and placenta. Brain had the highest activity followed by ovary, fetal brain, and placenta. BCATc was not found in fetal liver, adult rat liver, or a rat hepatoma cell line. These data provide clear evidence that BCATc, unlike BCATm, is restricted to several highly specialized tissues.
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PMID:Branched chain aminotransferase isoenzymes. Purification and characterization of the rat brain isoenzyme. 838 18

The present study reports on the usefulness of laparoscopic microwave coagulonecrotic therapy as a new option in the treatment of hepatocellular carcinoma. Five patients with liver tumors associated with cirrhosis were treated from July 1993 to March 1994 with a microwave electrode (output 100 W, 3 to 4 cm long) devised for laparoscopic use. The tumors, all with diameters less than 3 cm and superficially located, were coagulated for a total radiation period of 20 to 30 min under laparoscopic, intraoperative ultrasonographic control. Postoperative complications were negligible, and laboratory values (glutamate-pyruvate transaminase, bilirubin, prothrombin time, platelet count) returned to preoperative levels within 7 days. Complete necrosis, including the surrounding liver tissue, was confirmed by a follow-up dynamic computed tomography scan during the follow-up period of 6 to 17 months (mean, 13 months). Laparoscopic microwave coagulonecrotic therapy can exert an effect on tumor equivalent to that obtained from a wedge resection but is noninvasive and may represent a new option for unresectable liver cancers.
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PMID:Laparoscopic microwave coagulonecrotic therapy for hepatocellular carcinoma. 861 89


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