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)

Asparagine synthetase (L-aspartate:ammonia ligase (AMP-forming, EC 6.3.1.1) activity in rat liver increased when the animals were put on a low casein diet. The enzyme was purified about 280-fold from the supernatant of rat liver homogenate by a procedure comprising ammonium sulfate fractionation. DEAE-Sepharose column chromatography, and Sephadex G-100 gel filtration. The optimal pH of the enzyme was in the range 7.4-7.6 with glutamine as an amide donor. The molecular weight was estimated to be approximately 110,000 by gel filtration. Chloride ion was required for the enzyme activity. The apparent Km values for L-aspartate, L-glutamine, ammonium chloride, ATP, and Cl- were calculated to be 0.76, 4.3, 10, 0.14, and 1.7 mM, respectively. The activity was inhibited by L-asparagine, nucleoside triphosphates except ATP, and sulfhydryl reagents. It has been observed that the properties of asparagine synthetase from rat liver are not so different from those of tumors such as Novikoff hepatoma and RADA 1.
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PMID:Purification and properties of asparagine synthetase from rat liver. 2 63

Ochratoxin A has a number of toxic effects in mammals, the most notable of which is nephrotoxicity. It is also immunosuppressive, teratogenic and carcinogenic. The biochemical and molecular aspects of its action were first studied in bacteria. The appearance of 'magic spots' (ppGpp and pppGpp) pointed to inhibition of the charging of transfer ribonucleic acids (tRNA) with amino acids. This suggestion was confirmed by the demonstration that ochratoxin A inhibits bacterial, yeast and liver phenylalanyl-tRNA synthetases. The inhibition is competitive to phenylalanine and is reversed by an excess of this amino acid. As a consequence, protein synthesis is inhibited, as shown with hepatoma cells in culture, with Madin Darby canine kidney cells (which are much more sensitive) and in vivo in mouse liver, kidney and spleen, the inhibition being more effective in the latter two organs. An excess of phenylalanine also prevents inhibition of protein synthesis in cell cultures and in vivo. Analogues of ochratoxin A in which phenylalanine has been replaced by other amino acids have similar inhibitory effects on the respective amino acid-specific aminoacyl tRNA synthetases. 4R-Hydroxyochratoxin A, a metabolite of ochratoxin A, has a similar action, whereas ochratoxin alpha (the dihydroisocoumarin moiety) and ochratoxin B (ochratoxin A without chlorine) have no effect. Ochratoxin A might act on other enzymes that use phenylalanine as a substrate. We showed recently that it inhibits phenylalanine hydroxylase. In addition, the phenylalanine moiety of ochratoxin A is partially hydroxylated to tyrosine by incubation with hepatocytes and in vivo. This competitive action with phenylalanine might explain why this amino acid prevents the immuno-suppressive effect of ochratoxin A and partially prevents its teratogenic and nephrotoxic actions. The effect of ochratoxin A on protein synthesis is followed by an inhibition of RNA synthesis, which might affect proteins with a high turnover. Ochratoxin A also lowers the level of phosphoenolpyruvate carboxykinase, a key enzyme in gluconeogenesis; this inhibition is reported to be due to a specific degradation of mRNA that codes for this enzyme. Recently, ochratoxin A was also found to enhance lipid peroxidation both in vitro and in vivo. This inhibition might have an important effect on cell or mitochondrial membranes and be responsible for the effects on mitochondria that have been shown by several authors. Finally, the recent results of Pfohl-Leszkowicz et al. (this volume), who showed the formation of DNA adducts mainly in kidney but also in liver and spleen, explain the DNA single-strand breaks observed previously in mice and rats after acute and chronic treatment.
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PMID:Mechanism of action of ochratoxin A. 182 Mar 32

The rat hepatic cytosolic receptor binding affinities of 8-substituted 2,3-dichlorodibenzofurans and 8-substituted 2,3,4-trichlorodibenzofurans have been measured. The EC50-value for each compound was determined by dose-response competitive displacement of 2,3,7,8-[3H] tetrachlorodibenzo-p-dioxin (TCDD). Multiple parameter linear regression analysis of the data using several substituent parameters [lipophilicity (pi), hydrogen bonding (HB), electronegativity (sigma op), STERIMOL (delta B5)] demonstrated that for both sets of ligands, the binding affinities were dependent on substituent pi-values. The equations derived for the 8-substituted 2,3,4-trichlorodibenzofurans (a) and 8-substituted 2,3-dichlorodibenzofurans (b) were (Formula: see text) remarkably similar, moreover the relatively bulky t-butyl substituent was treated as an outlier for both calculations. The in vitro induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells by both sets of ligands demonstrated that there was not a rank order correlation between induction potencies and receptor binding affinities for these compounds. Analysis of the data for the 8-substituted 2,3-dichlorodibenofurans demonstrated that the monooxygenase enzyme induction was dependent on substituent lipophilicity and a STERIMOL (delta B5) factor which is related to (Formula: see text) substituent width. In contrast, the equation for the 8-substituted 2,3,4-trichlorodibenzofurans also included a substituent sigma op Hammett constant. The results indicate that although the binding affinities of the two sets of ligands are dependent only on substituent pi-values, their enzyme induction activities are both substituent and chlorine substitution pattern-dependent.
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PMID:Substituted polychlorinated dibenzofuran receptor binding affinities and aryl hydrocarbon hydroxylase induction potencies--a QSAR analysis. 300 35

The dose-response effects of 2,3,7,8-tetrachorodibenzo-p-dioxin, 1,3,7,8-tetrachlorodibenzo-p-dioxin, 1,2,4,7,8-pentachlorodibenzo-p-dioxin, 2,3,4,7,8-, 1,2,3,7,9-, and 2,3,4,7,9-pentachlorodibenzofuran on body weight loss and hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction were determined in the immature male guinea pig. The ED50 values for each compound were measured for the three in vivo responses. The quantitative structure-activity relationships clearly illustrated that the most toxic congeners were substituted in the lateral 2, 3, 7 and 8 positions, and removal of a lateral chlorine group substantially reduced the potency of the resulting compound. The most toxic congener in this series was 2,3,7,8-tetrachlorodibenzo-p-dioxin in which the in vivo ED50 values for AHH and EROD induction and body weight loss were 2.8 X 10(-10), 9.3 X 10(-11) and 5.6 X 10(-9) mol/kg. The structure-activity relationships observed in this study were comparable to those previously reported in rats and rat hepatoma H-4-II E cells in culture. Moreover, there was an excellent linear correlation between in vivo -log ED50 values for body weight loss, AHH and EROD induction and the corresponding in vitro -log EC50 data for AHH induction in rat hepatoma cells [S. Safe, Chemosphere 16, 791 (1987)].
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PMID:Biologic and toxic effects of polychlorinated dibenzo-p-dioxin and dibenzofuran congeners in the guinea pig. Quantitative structure-activity relationships. 335 83

There were marked effects of structure on the activities of 14 polychlorinated dibenzo-p-dioxins (PCDDs) as competitive ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor and as inducers of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II E cells in culture. 2,3,7,8-TCDD was the most active compound in both assays and several PCDD congeners which were fully substituted in the lateral 2, 3, 7 and 8 positions but also contained additional chlorosubstituents in non-lateral 1, 4, 6 and 9 positions were less active. It was also evident that there was a decrease in in vitro binding and induction activities with decreasing lateral chlorine substitution. Although comparable structure-activity relationships (SARs) for the PCDDs were observed for the induction and receptor binding assays, there was not a linear or rank order correlation between the 2 sets of data. Several in vivo biologic and toxic activities of 2,3,7-trichloro-, 2,3,7,8- and 1,3,7,8-tetrachloro-, 1,2,4,7,8- and 1,2,3,7,8-pentachloro- and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin were determined in a dose-response fashion in immature male Wistar rats. The ED50 values for hepatic microsomal AHH and EROD induction, body weight loss and thymic atrophy were obtained. There was an excellent linear correlation between the -log EC50 values for AHH or EROD induction in cell culture and the -log ED50 values for enzyme induction, body weight loss and thymic atrophy in the rat. The in vitro enzyme induction data could be used to quantitatively estimate the toxicity of the PCDD congeners in the rat: this latter correlation has previously been observed for a series of polychlorinated dibenzofurans.
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PMID:Polychlorinated dibenzo-p-dioxins: quantitative in vitro and in vivo structure-activity relationships. 375 Mar 36

Fifteen polychlorinated dibenzofuran (PCDF) congeners were administered in a dose-response fashion to immature male Wistar rats and ED50 values for body weight loss, thymic atrophy and the induction of the hepatic microsomal cytochrome P-448-dependent monooxygenases, aryl hydrocarbon hydroxylase (AHH) and 4-chlorobiphenyl hydroxylase were determined. There was an excellent correlation between the in vivo quantitative structure-activity relationships for these PCDFs and their in vitro activities as AHH inducers in rat hepatoma H-4-II E cells and as ligands for the 2,3,7,8-TCDD receptor protein. A comparison of isomers which differ at all 4 positions in the dibenzofuran ring system indicated that chlorine substitution at each position contributed differentially to the overall molecular activity [C-3 (or C-7) greater than C-2 (or C-8) greater than C-4 (or C-6) greater than C-1 (or C-9)]. There was also an excellent linear correlation between a plot of the -log ED50 for body weight loss vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.96) and -log ED50 for thymic atrophy vs. -log EC50 for in vitro AHH induction (correlation coefficient, r = 0.88). Since body weight loss and thymic atrophy in the rat are representative toxic responses to PCDFs and related toxic halogenated aryl hydrocarbons, the correlations noted above support the use of the in vitro AHH induction assay as a short term quantitative test system for this class of toxic halogenated aryl hydrocarbons.
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PMID:Polychlorinated dibenzofurans (PCDFs): correlation between in vivo and in vitro structure-activity relationships. 393 43

Aroclor 1254 and fireMaster BP-6, two commercial polychlorinated biphenyl (PCB) and polybrominated biphenyl (PBB) preparations, exhibit comparable biologic and toxic effects. In the present study the commercial PBB was more active than Aroclor 1254 in causing thymic atrophy in male Wistar rats. However, a direct comparison of the relative effects of bromine vs chlorine substituents is not possible with the commercial PBB and PCB mixtures due to their complex congeneric composition. This study reports the synthesis and biologic and toxic effects of a series of laterally substituted 3,3',4,4'-tetrahalobiphenyls which contain the following variable molecular Cl/Br ratios; Br4, Br3Cl, Br2Cl2 (two isomers), BrCl3, and Cl4. 3,3',4,4'-Tetrabromobiphenyl and 3,4,4'-tribromo-3'-chlorobiphenyl (150 mumol/kg)-pretreated animals significantly inhibited the growth rate of and caused thymic atrophy in immature male Wistar rats whereas those isostereomers with reduced Br (and increased Cl) content were either less active or inactive. Pretreatment of male Wistar rats with 10 mumol/kg of the 3,3',4,4'-tetrahalobiphenyls and determination of their effects as inducers of the hepatic microsomal drug-metabolizing enzymes also illustrated the effects of the relative Cl/Br ratios on induction potencies. Both 3,3',4,4'-tetrabromo- and 3,4,4'-tribromo-3'-chlorobiphenyl maximally induced the cytochrome P-448-dependent monooxygenases, benzo[a]pyrene and 4-chlorobiphenyl hydroxylase; the order of potency of the other isostereomers was 4,4'-dibromo-3,3'-dichloro- congruent to 3,4-dibromo-3',4'-dichlorobiphenyl greater than 4-bromo-3,3',4'-trichloro- greater than 3,3',4,4'-tetrachlorobiphenyl. With few exceptions this order of potency was observed for the induction of benzo[a]pyrene hydroxylase and ethoxyresorufin O-deethylase in rat hepatoma cells in culture and for their relative binding affinities to the rat cytosolic receptor protein. The data clearly demonstrate that the biologic activities of this group of isosteric halogenated biphenyls are enhanced with increasing bromine substitution and also support the hypothesis that the activities of this class of chemicals are mediated through the receptor.
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PMID:The comparative biologic and toxic potencies of polychlorinated biphenyls and polybrominated biphenyls. 631 30

The effects of structure on the activity of 26 polychlorinated dibenzofurans (PCDFs) as competitive ligands for the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) rat hepatic cytosolic receptor protein were determined in a dose-response fashion. The ED50 values for these compounds varied 100 000-fold and the most active PCDFs were substituted in the 2,3,7 and 8 lateral positions; the ED50 for the most active PCDF, 2,3,4,7,8-pentachlorodibenzofuran was 1.5 X 10(-8) M which was only slightly less active than 2,3,7,8-TCDD (1.0 X 10(-8) M). A comparison of the binding affinities of several isomer pairs also indicated the relative importance of chlorine substitution at C-4 (or C-6) compared to C-1 (or C-9). Moreover, for some isomers it is apparent that C-4 (or C-6) substituents are more active than lateral substituents for facilitating ligand binding to the receptor protein. This is illustrated by the relative binding potencies of the following isomer pairs: 1,2,4,6,7-/1,2,4,7,8 = 19.2; 2,6,7-/2,3,8- = 2.2; 1,3,6-/1,3,8- = 19. Most of the PCDF structure-activity effects noted above were also observed for the induction of aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) in rat hepatoma H-4-II-E cells in culture. The most active compounds were also substituted in the lateral 2,3,7 and 8 positions and a comparison of C-4 (or C-6) vs. C-1 (or C-9) substituted PCDFs confirmed the higher induction potencies for most of the former group of compounds. The in vitro quantitative structure-activity data were complemented by in vivo studies which determined the relative activities of selected PCDFs as inducers of hepatic microsomal cytochrome P-448 dependent monooxygenases and their effects on body weight gain and thymus weights in immature male Wistar rats. The results indicated that for 2 series of isomers, namely the 2,3,4,7,8-, 1,2,4,7,8- and 1,2,4,7,9-pentachlorodibenzofurans and the 2,3,7,8-, 2,3,4,8- and 1,2,4,8-tetrachlorodibenzofurans, their biologic and toxic potencies were dependent on one major structural factor, the number of lateral chloro substituents. These results support the proposed role of the cytosolic receptor protein in mediating the biologic and toxic effects of the PCDFs.
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PMID:Polychlorinated dibenzofurans (PCDFs): effects of structure on binding to the 2,3,7,8-TCDD cytosolic receptor protein, AHH induction and toxicity. 646 25

Energy-dispersive X-ray microanalysis was carried out on normal and regenerating liver as well as on 3924 A hepatoma cells. Specimens were quickly removed from the sacrificed animals, frozen in liquid isopentane, fractured still in the frozen state and freeze-dried under vacuum. The dried samples were examined in secondary electron image mode, and the X-ray spectra were recorded by means of an EDAX 707A system. Sodium and chlorine contents were higher both in nuclei and cytoplasms of regenerating and tumor hepatocytes than in normal liver. Moreover, hepatoma cells showed higher sodium and chlorine contents than did normal proliferating hepatocytes. Potassium contents did not show any differences among the experimental models. The increased sodium content and the resulting increased Na:K ratios of proliferating normal and tumor cells were not due to a generalized increase of these parameters in all the cells, but to the presence of new cell populations with high Na content and high Na:K ratios. Findings of present work are consistent with the hypothesis that high sodium content is associated with mitogenesis. Moreover, the much higher concentration of sodium in tumor cells as compared with normal proliferating hepatocytes supports the hypothesis that the concentration of this ion is related to oncogenesis of hepatocytes.
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PMID:X-ray microanalysis of monovalent electrolyte contents of quiescent, proliferating as well as tumor rat hepatocytes. 665 71

This study was designed to investigate the effects of a growing H6 hepatoma on the intracellular element content in three distinctly different tissue cell populations of the mouse host (hepatocytes, fibroblasts, and crystal enterocytes). X-ray microanalysis measurements of the intranuclear concentrations of several elements (sodium, magnesium, phosphorus, sulfur, chlorine, and potassium) were made. Briefly, the tumor presence significantly increased intranuclear sodium concentration but not the concentration of magnesium, phosphorus, sulfur, chlorine, or potassium in three tissue cell types of mice that were anorectic and cachectic. A second aim of the study was to see if injections of the diuretic amiloride, a drug reported to block passive influx of sodium into mammalian cells, would counteract the effect of the tumor presence and lower the intranuclear concentration of sodium towards that of a non-tumor-bearing host. Amiloride did significantly lower the intranuclear level of sodium in the host tissues to that of non-tumor-bearing mice. The amiloride-caused decrease on intracellular sodium was correlated to a decreased cell proliferation activity in the tumor cells and duodenal enterocytes. A possible relationship between the intracellular concentration of sodium in tissue cells and cancer cachexia is discussed.
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PMID:Effect of cancer cachexia and amiloride treatment on the intracellular sodium content in tissue cells. 682 79


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