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)

Pravastatin and pravastatin-lactone are not taken up into extrahepatic cells such as fibroblasts, or hepatoma cells such as AS-30D ascites hepatoma cells or FAO cells. In contrast, pravastatin is taken up into isolated rat hepatocytes by a carrier mediated, saturable, temperature-dependent and energy-dependent mechanism. The kinetic parameters for the saturable uptake are Km 27 microM, Vmax 537 pmol/mg per min. The permeability coefficients were determined to be 9.829 x 10(-7) cm/s at 4 degrees C, 1.76 x 10(-6) cm/s at 7 degrees C, 3.85 x 10(-6) cm/s at 17 degrees C and 5.82 x 10(-6) cm/s at 37 degrees C. The activation energy is 60 kJ/mol for 100 microM pravastatin at 37 degrees C. The Q10 values are between 1.7 and 2.8. In the presence of metabolic inhibitors and in the absence of oxygen, transport is inhibited. Uptake of pravastatin is not dependent on an extracellular to intracellular sodium-gradient. Replacement of chloride by sulfate, nitrate, gluconate or thiocyanate significantly inhibits the uptake of pravastatin. Uptake is competitively inhibited by cholate and taurocholate in the presence and absence of sodium. Pravastatin, however, competitively inhibits the uptake of cholate and taurocholate only in the absence of sodium. In addition, pravastatin-lactone enters liver cells via an energy-dependent, carrier-mediated uptake system. For the saturable energy-dependent part of the hepatocellular uptake a Km value of 9 microM and a Vmax value of 621 pmol/mg per min was determined. The permeability coefficient of pravastatin-lactone uptake is calculated to be 5.41 x 10(-6) cm/s at 37 degrees C. The uptake of pravastatin-lactone is competitively-noncompetitively inhibited by pravastatin and by lovastatin and vice versa. These results indicate that the hepatoselectivity of pravastatin is due to its carrier-mediated uptake into rat hepatocytes via a sodium-independent bile acid carrier. Pravastatin-lactone resembles pravastatin-sodium in its hepatoselectivity.
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PMID:Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone. 824 Dec 47

We have previously reported that the Kupffer cell has antitumor activity through mitochondrial damage to tumor cells by nitric oxide production. In this study, the effect of chronic ethanol feeding on antihepatoma cell activity of the Kupffer cell was examined in rats. Male rats of the Wistar strain were fed ethanol chronically for 8 weeks by liquid diets. Kupffer cells were isolated from the control rat or the ethanol-fed rat, and cocultured with AH 70 cells, a rat hepatoma cell line. Fluorescence of rhodamine 123 or propidium iodide was observed as indicators of the mitochondrial damage or cell membrane injury, respectively, by a laser scanning confocal microscopy. Mitochondrial damage of AH 70 cells as indicated by reduction of rhodamine 123 fluorescence was smaller by the coculture with Kupffer cell from the ethanol rat than that from the control. Cell membrane barrier dysfunction of AH 70 cell was less frequently observed with the Kupffer cell from ethanol-fed rats. A metabolite of nitric oxide (nitrite and nitrate) was less in the cultured medium with the ethanol Kupffer cell than with the control Kupffer cell. Ca2+ mobilization, which induces inducible nitric oxide synthase and observed by the fluorescence of fluo-3, in Kupffer cells cocultured with AH 70 cells was suppressed in ethanol-fed rats. These result suggests that chronic ethanol feeding suppresses antitumor cell activity of Kupffer cell through the impairment of Ca2+ mobilization and nitric oxide production.
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PMID:Effect of chronic ethanol feeding on Kupffer cell-mediated antitumor cell activity. 865 94

The present study was designed to monitor the process for hepatoma cell injury induced by Kupffer cells. The non-activated Kupffer cells isolated from male Wistar rats reduced the mitochondrial membrane potential in the cocultured AH70 cells, which was indicated by the decreased rhodamine 123 (Rh123) fluorescence. Increased level of nitrite and nitrate in the medium and induction of iNOS in Kupffer cells were observed after coculture with AH70 cells. Incubation with either NG-monomethyl-L-arginine or aminoguanidine attenuated the increased nitric oxide (NO) production of Kupffer cells and the decreased Rh123 fluorescence of AH70 cells. Fluo-3, a calcium-sensitive probe, fluorescence in Kupffer cells increased after coculture with AH70 cells. Addition of TMB-8, a calcium inhibitor, or monoclonal antibody directed against ICAM-1 or CD18 prevented the increases in fluo-3 fluorescence and NO production of Kupffer cells and Kupffer cell-induced mitochondrial dysfunction in AH70 cells, suggesting the involvement of calcium mobilization and CD18/ICAM-1. It is therefore suggested that the Kupffer cell-mediated mitochondrial dysfunction of hepatoma cells largely depends on NO production by iNOS, and that the NO production by Kupffer cells is triggered by CD18/ICAM-1-dependent interaction with hepatoma cells and subsequent calcium mobilization. In other series of experiments, male Wistar rats fed ethanol for 4 weeks were used. The NO production and calcium mobilization of Kupffer cells and reduction of the mitochondrial membrane potential in cocultured hepatoma cells were diminished in the case of Kupffer cells isolated from chronically ethanol-fed rats, while CD18 and ICAM-1 expression was still observed. Thus, the present study further suggests that NO-dependent anti-hepatoma cell activity of Kupffer cells is suppressed in chronically ethanol-fed animals.
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PMID:CD18/ICAM-1-dependent nitric oxide production of Kupffer cells as a cause of mitochondrial dysfunction in hepatoma cells: influence of chronic alcohol feeding. 895 49

Previous studies have indicated that nitric oxide (NO) released from Kupffer cells modulates biological viability of cocultured hepatoma cells. This study was designed to evaluate the mechanisms by which Kupffer cells synthesize and release NO in reponse to cocultured hepatoma cells. Kupffer cells isolated from male Wistar rats were cocultured with rat hepatoma cell line, AH70 cells. The sum of nitrite and nitrate levels increased in the culture medium of Kupffer cells with AH70 cells as compared with those of Kupffer cells or AH70 cells alone. Increased expressions of iNOS and iNOS mRNA in Kupffer cells cocultured with AH70 cells were detected by an immunofluorescence staining and a fluorescence in situ hybridization study, respectively. A fluorescence in situ DNA-protein binding assay revealed that NF-kappaB activation occurs in Kupffer cells and activated NF-kappaB moved into the nuclei preceding to an increased production of NO. Oxidative stress indicated by dichlorofluorescein fluorescence was observed in Kupffer cells cocultured with AH70 cells. An increased calcium mobilization indicated as increased fluo-3-associated fluorescence was also induced in Kupffer cells after coculture with AH70 cells. Monoclonal antibodies directed against rat CD18 and ICAM-1, as well as TMB-8, a calcium inhibitor, prevented the calcium mobilization, active oxygen production, and NF-kappaB activation in addition to the increased production of NO. Pyrrolidine dithiocarbamate, an inhibitor of oxidative NF-kappaB activation, diphenylene iodonium, an NADPH oxidase inhibitor, and quinacrine, a phospholipase A2 inhibitor, significantly attenuated the increase in dichlorofluorescein fluorescence, NF-kappaB activation, and NO production. Therefore, this study suggests that CD18/ICAM-1-dependent cell-to-cell interaction with hepatoma cells causes calcium mobilization and oxidative activation of NF-kappaB, which may lead to the increased production of NO in Kupffer cells.
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PMID:CD18/ICAM-1-dependent oxidative NF-kappaB activation leading to nitric oxide production in rat Kupffer cells cocultured with syngeneic hepatoma cells. 906 44

Human hepatoma cells (HepG2) were exposed to several heavy metal salts and the induction of heat shock protein 70 (hsp70) mRNA was analysed by the reverse transcriptase-polymerase chain reaction (RT-PCR). Metals were added to the cell medium at concentrations ranging from 0.1 to 100 microM and incubation was continued for 4 h. In addition we analysed the time dependence of hsp70 induction by adding each metal at a certain concentration followed by an incubation for 0.5 to 24 h. CdCl2, NaAsO2, AgNO3 could be classified as very strong inducers (20-, 13- and 10-fold above control level) and they reached their maximum level of induction at 1-10 microM after 2 h. CuCl2, MnCl2, Pb(NO3)2, TlNO3, CoCl2 and NiCl2 were also strong inducing agents, giving a 4-6 fold induction at 10-100 microM after 4-8 h. ZnSO4, Hg(NO3)2 and AlCl3 were only weak inducers (1.5-2 fold at 50-100 microM after 4-8 h) of hsp70 mRNA. Cytotoxic effects (measured by release of lactate dehydrogenase) could only be detected for 100 microM Hg2+ after 4 h and when the cells were incubated with 5 microM Cd2+ for more than 8 h. We also tested a few combinations of these heavy metal salts for their hsp70-inducing ability. Zn2+ and Mn2+ were able to diminish Cd2+ induced hsp70 mRNA levels by 65%. Ag+ mediated induction was reduced by 40% when combined with Cu2+, whereas Hg2+ increased induction by Ag+ about 3-fold and led to a dramatic decrease in cell viability. In our study we were able to demonstrate that the analysis of hsp70 mRNA levels in chemically stressed HepG2 cells by RT-PCR can be a valuable tool for studying mechanisms of toxicity associated with elevated expression of hsp70.
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PMID:Analysis of hsp70 mRNA levels in HepG2 cells exposed to various metals differing in toxicity. 982 Jun 63

Although nitric oxide (NO) has been postulated to play important roles in host defense mechanisms against tumor cells, a direct evidence supporting this hypothesis is lacking. To obtain molecular insights into the antitumor action of NO, its metabolism and effect on ascites hepatoma (AH-130) cells were investigated in tumor-bearing rats. Kinetic analysis revealed that substantial amounts of nitrite and nitrate, metabolites of NO, appeared in plasma and ascites of AH-130-inoculated rats. Western blot analysis revealed that a large number of macrophages that expressed inducible type of NO synthase (iNOS) appeared in cancerous ascites, particularly during 1 to 2 weeks after inoculation of AH-130 cells. When NO generation by peritoneal macrophages increased, a significant fraction of AH-130 in ascites fluid underwent apoptosis as judged from the fragmentation of their nuclear DNA. Kinetic analysis revealed that NO strongly inhibited mitochondrial electron transport and changed calcium status in AH-130 cells, particularly under low oxygen tensions such as in cancerous ascites. Intraperitoneal injection of NO donor strongly enhanced DNA fragmentation of AH-130 cells. Antimycin A, a specific inhibitor for mitochondrial electron transport, also induced DNA fragmentation of AH-130 cells by a mechanism that was inhibited by adding ascorbate and tetramethyl-p-phenylene diamine (TMPD) as electron donors. These results indicate that NO derived from peritoneal macrophages inhibits mitochondrial electron transport and disturbs calcium homeostasis in ascites hepatoma AH-130 cells, thereby inducing their apoptosis in vivo.
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PMID:Macrophage-derived nitric oxide induces apoptosis of rat hepatoma cells in vivo. 982 9

Since plasma concentrations of nitrite/nitrate, the stable end-products of nitric oxide, increase in patients with hepatocellular carcinoma (HCC) correlatively to tumor volume, we examined the ability of plasma nitrite/nitrate to discriminate between those patients with HCC and those without and compared the diagnostic performance of the parameter with that of serum alpha-fetoprotein (AFP) concentrations. Plasma nitrite/nitrate and serum AFP concentrations were measured using a Griess reaction and a solid phase enzyme immunoassay, respectively. Eighty-nine patients with chronic liver diseases (CLD) with (n=39) or without HCC (n=50) and 50 healthy control subjects participated in the study. A receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value and accuracy. The areas under ROC curves for nitrite/nitrate and AFP were calculated to be 0.758 and 0.812, respectively, which were not significantly different. There was no correlation between the concentrations of plasma nitrite/nitrate and serum AFP. The sensitivity, the specificity, and diagnostic efficiency were 79.5, 72.0, and 75.3%, respectively, for nitrite/nitrate, and 74.4, 76.0, and 75.3%, respectively, for AFP. Based on a partial ROC curve, the clinical utility of plasma nitrite/nitrate as a tumor marker approximated that of serum AFP, but exceeded in AFP-negative patients. Indeed, nitrite/nitrate was positive in 70% of AFP-negative HCC patients. The simultaneous determinations of serum AFP and plasma nitrite/nitrate concentrations gave significant improvement in detection of HCC in CLD patients compared with that of serum AFP alone.
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PMID:Plasma nitrite/nitrate concentrations as a tumor marker for hepatocellular carcinoma. 1080 81

2,4-dichlorophenoxyacetic acid (2,4-D) and nitrate are agricultural contaminants found in rural ground water. It is not known whether levels found in groundwater pose a human or environmental health risk, nor is the mechanism of toxicity at the molecular/cellular level understood. This study focused on determining whether 2,4-D or nitrate at environmentally realistic levels elicit gene expression changes in exposed cells. cDNA microarray technology was used to determine the impact of 2,4-D and nitrate in an in vitro model of exposure. Human hepatoma HepG2 cells were incubated with 2,4-D or nitrate alone for 24 h. Cell viability (neutral red assay) and proliferation (BrdU incorporation) were assessed following exposure. Total RNA from treated and control cells were isolated, reverse transcribed and reciprocal labelled with Cy3 or Cy5 dyes, and hybridized to a human cDNA microarray. The hybridized microarray chips were scanned, quantified and analyzed to identify genes affected by 2,4-D or nitrate exposure based on a two-fold increase or decrease in gene expression and reproducibility (affected in three or more treatments). Following filtering, normalization and hierarchical clustering initial data indicate that numerous genes were found to be commonly expressed in at least three or more treatments of 2,4-D or nitrate tested. The affected genes indicate that HepG2 cells respond to environmental, low-level exposure and produce a cellular response that is associated with alterations in the expression of many genes. The affected genes were characterized as stress response, cell cycle control, immunological and DNA repair genes. These findings serve to highlight new pathway(s) in which to further probe the effects of environmental levels of 2,4-D and nitrate.
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PMID:Altered gene expression in human hepatoma HepG2 cells exposed to low-level 2,4-dichlorophenoxyacetic acid and potassium nitrate. 1587 51

Hepatocellular carcinoma (HCC) ranks fifth in frequency of cancers worldwide. The main aetiological factor is hepatitis B virus (HBV) although the importance of hepatitis C virus (HCV) is growing. The most important tumour marker for HCC is alpha-fetoprotein (AFP). The common method of screening high risk patients by AFP and ultrasonography has been shown to result in earlier detection and consequently more easily treatable tumours and longer survival. Proposed screening interval varies from once every 3 months to annually to "as indicated' but, most commonly, is once every 6 months. AFP is a fairly specific but insensitive marker for HCC. Sensitivity of HCC detection by blood markers is improved by combining various other markers with AFP. Of the other markers, the newer high sensitivity des-gamma-carboxy-prothrombin (DCP) has been found to be useful. In addition the AFP fractions L3, P4/5 and the +II band are highly specific for HCC. Among routinely assayed tumour markers in the laboratory, CA 125 is more sensitive for HCC than AFP but far less specific. Various other enzymes, isoenzymes, growth factors, adhesion molecules, other proteins such as interleukin-2 receptor (IL-2R), human cervical cancer oncogene protein (HCCR) and glypican-3 (GPC3), p15 and p16 hypermethylation and nitrite/nitrate ratio have been tested; some of these show promise but none is presently in routine use. The value of other newer markers such as the HBx protein that is produced by HBV, and what are thought to be specific proteins and signatures identified by proteomics remain to be determined.
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PMID:Recent developments in the first detection of hepatocellular carcinoma. 1645 14

The in vitro toxicological index IC50 (the millimolar concentration of compound which inhibits response assay by 50% compared to the solvent control) of 11 water contaminants (acrylamide, atrazine, B[a]P, BPA, 2,4-DAT, 17-alphaEE, H(2)O(2), 4-OP, sodium bromate, sodium chlorate, sodium nitrate) was evaluated on the human hepatoma (HepG2) cells using three short-term bioassays related to their morbidity status [radiometric RNA synthesis assay (RNA), luminometric ATP assay (ATP), fluorometric Alamar blue assay (AB)]. Among all substances, we were not able to determine atrazine IC50 value whatever the test used. Furthermore, B[a]P was not cytotoxic in the ATP and AB assays. Statistical analysis revealed a correlation between the IC50 values obtained in the three assays. Except with 4-OP, RNA assay was always inhibited at lower concentrations than those required in the other assays, suggesting that this assay is a very sensitive indicator of the presence of toxic compounds. ATP and AB assays responded to a similar pattern. Due to its higher sensitivity and its reliability, RNA synthesis assay using HepG2 cell line provides the most suitable tool for the screening of water contaminants.
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PMID:Evaluation of the sensitivity of three sublethal cytotoxicity assays in human HepG2 cell line using water contaminants. 1693 Jul 99


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