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)

M. glutinosa is a cyclostome, living in the mud in seawater of high salinity. It probably is a stationary scavenger feeder. About 28,000 hagfish from the Gullmar Fjord were examined during a 5-year period for the occurrence of tumors. Hepatomas were found to be predominant neoplasm, observed at a frequency that decreased from 5.8% in 1972 to 2.9% in 1973 and finally to 0.6% in 1974--76. Islet cell hamartomas and frank neoplasms decreased from 0.5% in 1972 to less than 0.1% in 1973--76. Occasional subcutaneous and mesenterial neoplasms were also observed during 1972--74. In hagfish caught 12 km out in the open sea, the hepatoma incidence decreased from 2.8% in 1972 to 0.9% in 1974. Given this background, it is possible that pollution of the Gullmar Fjord by carcinogenic substances with low biodegradability has occurred until 1972, and this pollution could be of etiologic significance for these hagfish tumors. In fact, the use of PCBs became prohibited by law in Sweden in 1971--72. Severe restrictions were also introduced for the use of chlorinated pesticides, notably DDT, and associated substances (DDD, DDE). Preliminary analyses for the presence of PCBs, DDT (and its metabolites), and aflatoxins (the notorious hepatocarcinogen) were performed by gas chromatography and thin-layer chromatography. Livers (with and without neoplasms) from hagfish caught inside the threshold of the fjord contained about 5 mg/kg of wet weight of PCBs and about 0.1--0.4 mg/kg of dry weight of DDT, DDD, or DDE, whereas those from hagfish caught in the open sea had a much lower PCB concentration (about 0.2 mg/kg of wet weight). No PCBs and no chlorinated pesticides were found in analyses of the mud at the catching site. High PCB concentrations (3 mg/kg of wet weight) were, however, observed in livers from cod living in the Gullmar Fjord, and it was proposed that bony fish may be the source of hagfish liver PCBs. PCB chromatograms of hagfish livers differed from those of PCB standards and cod liver. This strange pattern, which was not seen in livers from hagfish caught in the open sea, might be explained by an unusual mode of metabolization. The assays for aflatoxins gave completely negative results.
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PMID:Hepatomas and other neoplasms in the atlantic hagfish (Myxine glutinosa): a histopathologic and chemical study. 21 94

PCBs are compounds whose physical/chemical properties led to their wide spread commercial use. The persistence and stability of PCBs have resulted in a world wide distribution. PCDFs, ones of PCB derivatives, are primary causal agents of mass food poisoning, called Yusho in Japan and Yu-Cheng in Taiwan. Several epidemiologic studies on the carcinogenicity of PCBs in both occupational exposure and accidental intoxication suggest that PCBs might be a potent carcinogen in liver and lung. Many investigators reported that PCBs induced hepatocellular carcinoma in rat and mice. Although either mutagenic or genotoxic effects of PCBs are not definite, their tumor promoting effects have been repeatedly demonstrated in the liver. The effects of PCBs as tumor promoter in the lung have also been reported. PCB congeners that efficaciously promote carcinogenesis increase cytochrome P-450-dependent monooxygenases, which are abundant both in bronchiolar Clara cells and in hepatocytes. PCB congeners which are inducers of P-450 may be active as tumor promoter by inhibiting intercellular communication and/or by stimulating cell proliferation. Furan derivatives like PCDFs have high affinity to bronchiolar Clara cells and hepatocytes. PCDFs induce necrosis and epoxide formation to their target cells, which might result in carcinogenesis of liver and lung.
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PMID:[Carcinogenic effects of polychlorinated biphenyls (PCBs) and their derivatives, including carcinogenicity to the lung]. 191 96

Halogenated aromatic industrial compounds, typified by the polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) have been identified as residues in almost every component of the global ecosystem. Risk assessment of the complex mixtures of halogenated aromatics found in environmental samples is complicated by analytical problems and the lack of toxicological information on individual compounds and mixtures. Research in our laboratory has focused on the development and vadidation of the in vitro aryl hydrocarbon hydroxylase (AHH) induction assay in rat hepatoma H-4-II E cells in culture for quantitating individual toxic halogenated aryl hydrocarbons and their mixtures. For several PCB, PCDD, PCDF congeners, their mixed bromo/chloro analogs and reconstituted mixtures there was an excellent linear correlation between their -log ED50 values for AHH induction in rat hepatoma cells and their -log ED50 values for in vivo hepatic microsomal AHH induction, inhibition of body weight gain and thymic atrophy in the rat. It has also been shown for selected compounds that there was a good correlation between their in vitro AHH induction potencies and their effects in guinea pigs (AHH induction, inhibition of body weight gain) and mice (immunotoxicity). This assay system has been utilized to quantitative the "2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) equivalents" present in extracts from diverse sources including fly ash from a municipal incinerator and pyrolyzed brominated flame retardants which contain a complex mixture of halogenated dibenzo-p-dioxins and dibenzofurans.
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PMID:Development and validation of in vitro induction assays for toxic halogenated aromatic mixtures: a review. 268 22

The toxicity and carcinogenicity of number of chemicals, for which there are toxicity and/or carcinogenicity data in mouse and rat, were tested in medaka, a small aquarium fish (Oryzias latipes). The water-soluble chemicals were dissolved in the water and the water-insoluble chemicals were incorporated into the diet. Observation for 24 wk revealed induction of liver cell carcinoma by 6 chemicals; aflatoxins B1 and G1, sterigmatocystin, ortho-aminoazotoluene, methylazoxymethanol acetate and N-nitrosodiethylamine. In medaka fed PCB or DDT only preneoplastic liver cell nodules were observed. No evident carcinogenicity was found in medaka treated with 2-fluorenylamine, 2-fluorenylacetamide, DL-ethionine, luteoskyrin, ochratoxin A, phenobarbital, 1-(2-tetrahydrofuryl)-5-fluorouracil, sodium benzoate, 2,3,4,5,6-penta-O-acetyl-D-gluconyl isothiocyanate, citrinin and fusarenon X, respectively, although toxic lesions or hyperplastic changes were demonstrated histologically. These results confirm the practical utility and rapidity of the use of medaka for screening carcinogenicity and toxicity of chemicals, since neoplastic or toxic morphological changes develop rapidly following administration of relatively small quantities of test materials.
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PMID:Usefulness and rapidity of screening for the toxicity and carcinogenicity of chemicals in medaka, Oryzias latipes. 716 69

Hepatic uroporphyria is a well-known effect of halo- genated aromatic hydrocarbons in mammalian and avian systems, including primary cell cultures, but attempts to produce uroporphyria in vertebrate (mammalian) hepatoma lines have been unsuccessful. In this study, the ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), and selected chlorobiphenyl congeners to cause uroporphyria was examined in a fish hepatoma cell line (PLHC-1) that expresses aryl hydrocarbon (Ah) receptors and an inducible cytochrome P4501A (CYP1A). Dose-dependent accumulation of porphyrins was observed in cells treated for 48 h with TCDD or 3,3',4,4'-tetrachlorobiphenyl (3,3',4,4'-TCB; IUPAC 77) when the heme precursor delta-aminolevulinic acid (ALA) was present during the last 5 h of treatment. HPLC analysis identified the porphyrins as uroporphyrin (approximately 80%) and heptacarboxylporphyrin (approximately 20%). Uroporphyria did not occur in cells treated with TCDD or 3,3',4,4'-TCB in the absence of added ALA. ALA-dependent porphyrin accumulation was also seen following treatment of PLHC-1 cells with TCDF or with the non-ortho-substituted chlorobiphenyls 3,4,4',5-tetrachlorobiphenyl (IUPAC 81) and 3,3',4,4',5-pentachlorobiphenyl (IUPAC 126). Neither of the mono-ortho-substituted chlorobiphenyls 2,3,3',4,4'-pentachlorobiphenyl (IUPAC 105) or 2,3',4,4'5-pentachlorobiphenyl (IUPAC 118) increased the porphyrin content of PLHC-1 cells. The ability of the PCB congeners to cause porphyria correlated with their ability to induce the CYP1A catalytic activity ethoxyresorufin 0-deethylase (EROD) and immunodetectable CYP1A protein in these cells, suggesting direct or indirect regulation of porphyrin accumulation via the Ah receptor and/or the induced CYP1A. Induction of EROD activity by TCDD, TCDF, and the planar polychlorinated biphenyls was biphasic, with increases at lower concentrations of inducer followed by decreased induction at higher concentrations, as seen previously. EC50 values for porphyrin accumulation were similar to, or slightly higher than, the concentrations at which peak EROD activities were obtained, suggesting a relationship between the decline in EROD activity and enhanced porphyrin accumulation. alpha-Naphthoflavone inhibited TCDD-induced EROD activity and porphyrin accumulation, providing further evidence for the involvement of a fish CYP1A in the mechanism of this prophyria. Addition of 3,3',4,4'-TCB to TCDD-treated cells also inhibited EROD activity, but enhanced porphyrin accumulation, suggesting that an interaction between the halogenated inducer and the induced CYP1A is necessary for the porphyrogenic response. PLHC-1 cells grown in medium supplemented with ALA may be a useful model System for studying mechanisms of chemical uroporphyria induced by Ah receptor agonists.
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PMID:Uroporphyrin accumulation associated with cytochrome P4501A induction in fish hepatoma cells exposed to aryl hydrocarbon receptor agonists, including 2,3,7,8-tetrachlorodibenzo-p-dioxin and planar chlorobiphenyls. 863 48

A recombinant H4IIE rat hepatoma cell line (H4L1.1c4, H4IIE-luc), containing a luciferase reporter gene under control of dioxin-responsive enhancers, was examined for responsiveness to several polyhalogenated aromatic hydrocarbons (PHAHs). The recombinant cell system was compared with the widely used wild-type cell line (H4IIE-wt), which expresses Ah receptor-mediated cytochrome P450 1A induction. We also report an improved and down-scaled method for the H4IIE-wt bioassay which allows for the rapid screening of environmental samples for Ah-active PhAHs. This method employs 96-well plates, a plate-reading spectrofluorometer, and a fluorescence-based protein assay that enables the simultaneous measurement of resorufin and protein. Both cell lines demonstrated a dose-dependent increase in Ah receptor-mediated response upon exposure to a number of known Ah receptor agonists, including Halowax 1014. H4IIE-luc cells were 3-fold more sensitive than H4IIE-wt cells to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The detection limit and ED50 for EROD induction by TCDD were 0.6 and 4.9 fmol/well (2,4 and 20 pM), respectively; for luciferase induction they were 0.2 and 1.4 fmol/well (0.8 and 5.6 pM). The detection limit for EROD induction in H4IIE-wt cells was a 50-fold improvement over that reported previously (Tillitt et al., Environ. Sci. Technol. 25, 87-92, 1991) and comparable to that of a chicken embryo primary hepatocyte bioassay (Kennedy et al., Anal. Biochem. 211, 102-112, 1993). The tested PHAHs exhibited a similar structure-activity relationship in H4IIE-luc as in H4IIE-wt cells. Binary mixtures of TCDD, PCB-126, and PCB-77 showed no departure from additivity in their combined responses when tested in H4IIE-wt cells. PCB-153 at the highest tested dose of 14 nmol/well (56 microM) significantly reduced the potency of TCDD and PCB-126 without affecting their efficacy in both H4IIE-wt and H4IIE-luc cells. These findings support the use of H4IIE-luc cells as an alternative bioanalytical tool to the wild-type cells for the detection of Ah agonists in environmental samples.
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PMID:Comparison of Ah receptor-mediated luciferase and ethoxyresorufin-O-deethylase induction in H4IIE cells: implications for their use as bioanalytical tools for the detection of polyhalogenated aromatic hydrocarbons. 866 58

This study demonstrates that the novel in vitro CALUX (chemical-activated luciferase expression) assay is a rapid, sensitive assay for assessing the toxic potency of (mixtures of) aryl hydrocarbon receptor (AhR)-active compounds in sediments and pore waters. A rat hepatoma (H4IIE) cell line, stably transfected with a construct containing the dioxin-responsive element (DRE) sequence and the luciferase reporter gene, was used to determine the relative potency or the total activities of AhR-active compounds in sediment and pore water extracts. This novel CALUX assay had a detection limit of 0.5 fmol of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The sensitivity and linear working range was slightly better than for the ethoxyresorufin O-deethylase (EROD) assay in H4IIE wild type cells. The primary improvement of the CALUX assay compared to the EROD assay, however, is that the CALUX assay is insensitive to substrate inhibition. The CALUX activity induced by organic extracts from 450-mg aliquots of sediment or 250-microl aliquots of pore water corresponded with the instrumentally analyzed degree of pollution of the sediment. Using pore water, only a simple and rapid extraction procedure was needed, without additional clean-up to prevent cell death. The response from pore water samples in an 8-day early life stage test with zebra fish (Branchydanio rerio) corresponded with the CALUX induction, although the correlation was sometimes disturbed by heavy metals. Two polychlorinated terphenyl mixtures, the PCB-substitute Ugilec 141, polybrominated diphenylethers, and the PCB-mixture Clophen A50 were tested in the CALUX assay and had induction potencies that were 10(-4)-10(-7) compared to TCDD.
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PMID:Chemical-activated luciferase gene expression (CALUX): a novel in vitro bioassay for Ah receptor active compounds in sediments and pore water. 881 60

Interaction of tributyltin (TBT) with 3,3',4,4',5-pentachlorobiphenyl (PCB-126)-induced ethoxyresorufin O-deethylase (EROD) activity was examined in vitro using H4IIE rat hepatoma cells. H4IIE cells were exposed to TBT and PCB-126, individually or in combination, at different concentrations. TBT was cytotoxic at concentrations greater than 98 nM. PCB-126 was not cytotoxic in the concentration range of 49 to 3140 pM. At concentrations greater than 49 nM, PCB-126 enhanced the cytotoxicity of TBT in the 24-98 nM range. In the absence of inducers of EROD activity, TBT significantly inhibited constitutive EROD activity in H4IIE cells in a concentration-dependent manner. EROD activity in H4IIE cells was significantly increased by exposure to PCB-126 alone. This effect was potentiated by coexposure to low, noncytotoxic concentrations of TBT. The induction of cytochrome P-4501A (CYP1A) activity in the presence of both an inducer (PCB-126) and low concentrations of an inhibitor (TBT) indicates that TBT does not interfere with the Ah receptor binding, but acts at the transcriptional level. Potentiation of EROD activity and cytotoxicity as a consequence of coexposure to PCB-126 and TBT is of considerable toxicological significance, given their coaccumulation in a variety of marine organisms.
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PMID:Interaction of tributyltin with 3,3',4,4',5-pentachlorobiphenyl-induced ethoxyresorufin O-deethylase activity in rat hepatoma cells. 982 60

The effects of many chemicals on cellular processes are governed by their ability to enter the cell, which is in turn a function of the composition of the cell's external environment. To examine this relationship, the effect of serum in cell culture medium on the bioavailability of cytochrome P450 1A (CYP1A)-inducing compounds was determined in PLHC-1 (Poeciliopsis lucida hepatocellular carcinoma) cells. The presence of 10% calf serum in the medium increased the EC50 (effective concentration to achieve 50% maximal response) for induction of ethoxyresorufin O-deethylase (EROD) activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 20-fold as compared to treatment in serum-free medium. Measurement of [3H]TCDD uptake and Ah receptor binding indicated that the apparent difference in potencies was a result of decreased bioavailability in the presence of serum, effectively reducing the concentration of TCDD within the cells. Induction of EROD and CYP1A protein in response to treatment with each of three coplanar polychlorinated biphenyls (PCB congeners 77, 126, and 169) was similarly affected by serum, although the magnitude varied among inducers and assays. Relative potencies (calculated as EC50TCDD / EC50PCB) for EROD induction by the three PCBs were significantly higher in the absence of serum. However, serum showed no significant effect on the relative potencies for CYP1A protein induction. These results demonstrate that measured inducing potencies, and relative potencies for EROD induction, by halogenated aromatic hydrocarbons are strongly dependent on the composition of culture medium, which can lead to artificial differences in comparisons among cell types.
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PMID:Serum alters the uptake and relative potencies of halogenated aromatic hydrocarbons in cell culture bioassays. 1069 80

In mammals, the toxicity of halogenated aromatic hydrocarbons (HAH) correlates with their ability to activate the aryl hydrocarbon receptor (AHR). To test this correlation in an avian model, we selected six HAHs based on their affinity for the mammalian AHR, including: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD); 2,3,7,8-tetrachlorodibenzofuran (TCDF); 2,3,4,7,8-pentachlorodibenzofuran (PCDF); 3,3',4,4'-tetrachlorobiphenyl (PCB 77); and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153). We determined the ability of these compounds to induce cardiotoxicity, as measured by an increase in heart wet weight on incubation day 10 in the chick embryo (Gallus gallus) and formation of the avian AHR/ARNT/DNA binding complex in chicken hepatoma cells. Relative potency values (RPs) were calculated by dividing the TCDD EC(50) (AHR/ARNT/DNA binding) or ED(50) (15% increase in day-10 heart wet weight) by the HAH congeners EC(50) or ED(50), respectively. The rank order of potencies for inducing cardiotoxicity were TCDD > PCDD = PCDF = TCDF > PCDF > PCB77, PCB 153, no effect. The RP values for inducing AHR/ARNT DNA binding were then correlated with those for inducing cardiotoxicity (the RP values of PCDD were determined to be statistical outliers). This correlation was found to be highly significant (r = 0.94, p = 0.017). The ability of PCDD to act as an AHR agonist was verified using luciferase reporter assays and analysis of cytochrome P4501A1 protein levels. These results indicate that the ability of HAHs to activate the avian AHR signaling pathway, in general, correlates with their ability to mediate cardiotoxicity in the chick embryo.
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PMID:Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. 1129 89


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