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)

Arachidonic acid (AA), a prostaglandin precursor, significantly potentiated sister-chromatid exchange (SCE) induction in vitro by benzo[a]pyrene (BP) and 7,12-dimethylbenz[a]anthracene (DMBA) in the aryl hydrocarbon hydroxylase (AHH)-inducible human hepatoma C-HC-4 cells, and to a lesser extent in the non-inducible rat tumor AH66-B and R1 and Chinese hamster Don-6 cells, all of which were less sensitive to these compounds than C-HC-4 cells. Indomethacin (IM), an inhibitor of prostaglandin endoperoxide synthetase (PES), moderately suppressed SCE induction by BP or DMBA in AH66-B and R1 cells, but it exerted no such effect in C-HC-4 and Don-6 cells. In C-HC-4 cells, however, IM completely eliminated the potentiating effect of AA on SCE induction by both BP and DMBA. The above findings suggest that PES in prostaglandin biosynthesis may also be involved in the metabolic activation of polycyclic aromatic hydrocarbons to genotoxic forms capable of inducing SCEs, in addition to AHH system.
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PMID:Effects of arachidonic acid and indomethacin on sister-chromatid exchange induction by polycyclic aromatic hydrocarbons in mammalian cell lines. 300 16

In laboratory animals and in mouse hepatoma cells in culture the Ah receptor previously has been shown to mediate induction of aryl hydrocarbon hydroxylase (cytochrome P1-450) by 3-methylcholanthrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. We examined human lung cytosols to determine whether the Ah receptor was present in human tissues. Cytosol was prepared from grossly normal lung tissue obtained at pulmonary lobectomy for presumed lung cancer from 53 consecutive adult patients including 32 males (42-77 years old) and 21 females (18-81 years old). Ah receptor in the cytosols was identified and quantitated by specific binding of [3H]TCDD after separation by ultracentrifugation on sucrose gradients. Specific binding of [3H]TCDD to a component which met the criteria for Ah receptor was detected in 10 of the 53 specimens. As previously established in tissues from laboratory animals, the specific [3H]TCDD-binding component sedimented approximately 9S. Binding of [3H]TCDD to the 9S component was competitively inhibited by incubation in the presence of 2,3,7,8-tetrachlorodibenzofuran, dibenz(a,h)anthracene, and nonradioactive TCDD, all known to be potent agonists for Ah-receptor-mediated induction of aryl hydrocarbon hydroxylase. Specific Ah receptor also was detected in some specimens by direct binding of [3H]-3-methylcholanthrene. The human population studied exhibited striking heterogeneity in Ah receptor concentrations. Only 10 of the 53 individuals studied had detectable Ah receptor. In specimens with detectable specific binding, the mean concentration of binding sites was 6.9 +/- 1.2 (SE) fmol/mg cytosolic protein. These concentrations are approximately 10-30% of the concentrations of Ah receptor found in lung cytosols from laboratory animals. Our experiments indicate that the Ah receptor can be detected in lung cytosol from some humans and suggest that the regulatory mechanism mediating human cytochrome P1-450 induction may be similar to that in the murine model. Aryl hydrocarbon hydroxylase, the major enzyme induced under control of the Ah receptor, plays an important role in the metabolism of several carcinogens including polycyclic aromatic hydrocarbons such as benzo(a)pyrene. It is possible that differences in the Ah receptor content within the human population may be genetically based and that variation at the Ah receptor level may be an important determinant of individual susceptibility to certain chemically induced cancers.
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PMID:Ah receptor mediating induction of aryl hydrocarbon hydroxylase: detection in human lung by binding of 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin. 301 Dec 54

The human hepatoma cell line Hep G2 was used to activate promutagenic chemicals to mutagens in a modified Salmonella typhimurium reversion assay. Hep G2 cells mediated positive mutagenic responses in tester strain TA98 with 5 and 25 micrograms/plate of 2-aminofluorene, but these responses were consistently lower than those seen using primary rat hepatocytes. In addition, 3 and 6 X 10(6) Hep G2 cells per assay produced positive mutagenic responses with 2-aminoanthracene, benzidine, acetylbenzidine and aflatoxin B1, while benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, 4-aminobiphenyl and 4- and 11-aminobenzo[a]pyrene were nonmutagenic with Hep G2-cell activation. These results indicate that Hep G2 cells may be a useful intact cellular metabolizing system of human origin for predicting the genotoxicity of promutagenic agents, but that the use of Salmonella as a target cell may limit the classes of mutagens detected.
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PMID:Use of the human liver cell line Hep G2 in a modified Salmonella reversion assay. 302 22

The dose-response rat hepatic cytosolic receptor-binding avidities, aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (EROD) induction potencies in rat hepatoma H-4-II E cells in culture were determined for 29 polynuclear aromatic hydrocarbons. It was apparent that the magnitude of the EC50 values for these in vitro responses were strongly dependent on structure. Dibenz[a,h]anthracene (1.6 X 10(-8) M), 7-methylbenz[a]anthracene (1.6 X 10(-8) M), 3-methylcholanthrene (2.8 X 10(-8) M) and picene (4.5 X 10(-8) m) exhibited the highest affinity for the receptor protein and these compounds were only 5-fold less active the 2,3,7,8-tetrachlorodibenzo-p-dioxin (1 X 10(-8) M). All of the compounds which were active in the receptor-binding and monooxygenase enzyme-induction assays possessed one common structural feature, namely the presence of a phenanthrene structure fused with at least 1 benzo ring. The results also demonstrated that there was not any apparent correlation between the receptor-binding avidities and in vitro monooxygenase enzyme-induction potencies for the most active polynuclear aromatic hydrocarbons.
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PMID:The cytosolic receptor binding affinities and AHH induction potencies of 29 polynuclear aromatic hydrocarbons. 302 61

The relative competitive binding affinities of benzo[a]pyrene (B[a]P), benzo[e]pyrene, benzo[g, h, i]perylene, picene, 7,12-dimethylbenz [a]anthracene, 1,2,3,4-dibenz[a]anthracene, 1,2,5,6-dibenz[a]anthracene, perylene, 4H-cyclopenta[d,e,f]-phenanthrene, benz[a] anthracene, triphenylethylene and triptycene for the rat hepatic cytosolic 4S binding protein were determined using [3H]benzo[a]pyrene as the radioligand. With the exception of triphenlethylene, triptycene and 4H-cyclopenta[d,e,f]phenanthrene, the EC50 values for the remainder of these compounds were between 1.25 X 10(-7) and 2.5 X 10(-8) M with 1,2,5,6-dibenz[a]anthracene being the most active ligand. A comparison of the relative cytosolic Ah (9S) receptor binding affinities and aryl hydrocarbon hydroxylase (AHH) induction potencies of these hydrocarbons with their 4S protein binding affinities demonstrated the following: five compounds, namely 1,2,5,6-dibenz[a]-anthracene, 1,2,3,4-dibenz[a]anthracene, picene, benzo[a]pyrene and 3-methylcholanthrene exhibited high to moderate binding affinities for the 4S and 9S cytosolic proteins (EC50 values less than 10(-6) M) and induced AHH in rat hepatoma cells; three compounds, namely perylene, benzo[e]pyrene and benzo[g,h,i]perylene exhibited high affinities for the 4S binding protein (1.25 X 10(-7), 4.4 X 10(-8) and 2.9 X 10(-8) M, respectively) and low affinities (EC50 values greater than 10(-5) M) for the Ah receptor protein; moreover these three compounds did not induce AHH in rat hepatoma H-4-II E cells in culture. These data suggest that the 4S binding protein may not play a significant role in AHH induction although the results do not rule out a function for this protein in the transregulation of AHH and its associated cytochromes P-450.
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PMID:Binding of polynuclear aromatic hydrocarbons to the rat 4S cytosolic binding protein: structure-activity relationships. 302 5

Two fat soluble vitamins, Vitamins E and K, when added into culture medium, were found to increase aryl hydrocarbon hydroxylase activity in human cultured cells. The extent of induction in a hepatoma-derived cell line (Hep G2) by these vitamins is of similar magnitude to those cells receiving benz[a]anthracene; whereas in a mammary tumor-derived cell line (MCF-7), benz[a]anthracene is the best inducer for the hydroxylase activity. The increase of the hydroxylase activity is associated with increased levels of a specific mRNA coding for polynuclear aromatic hydrocarbons-induced form of cytochrome P-450 with Vitamins E and K treatment. The size of the induced mRNA is 3.3 kilobase which is the same as that of benz[a]anthracene treatment.
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PMID:Vitamins E and K induce aryl hydrocarbon hydroxylase activity in human cell cultures. 303 86

A mouse hepatoma cell line, Hepa-1, is highly sensitive to the toxic effects of Aflatoxin B1 (AFB1). Half maximal survival (LD50) of cells occurs at 0.068 ug AFB1/ml. Benzo(a)anthracene, which induces aryl hydrocarbon hydroxylase and cytochrome P1-450 in Hepa-1, causes a slight increase in the toxicity of AFB1 (LD50 = 0.034 ug/ml). An aryl hydrocarbon hydroxylase- and cytochrome P1-450-deficient mutant of Hepa-1 is, however, over 100 times more resistant to AFB1 than Hepa-1. Almost no decline in survival is observed at 5 ug AFB1/ml. Cytochrome P1-450 thus effects strongly on the cytotoxicity of AFB1 in these cells. The basal activity in Hepa-1 is enough to elicit an almost full toxic effect. AFB1, although a substrate for cytochrome P1-450, does not act as an inducer of aryl hydrocarbon hydroxylase.
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PMID:Mechanism of cytotoxicity of aflatoxin B1: role of cytochrome P1-450. 310 20

Enzymatic activation of polycyclic aromatic hydrocarbons (PAHs) and its effect on cytotoxicity were studied using the neutral red viability assay as the end point. Benzo[a]pyrene was progressively cytotoxic to human hepatoma (HepG2) cells over a 1- to 3-d period, and after induction of monooxygenase activity with a polychlorobiphenyl (PCB) mixture (Arochlor 1254), cytotoxicity was increased about threefold. Concomitant with Arochlor exposure was an increase in the activity of 7-ethoxycoumarin odeethylase, which could be inhibited by exposure to alpha-naphthoflavone. Human keratinocytes (NHEK), but not fibroblasts (HFF), were sensitive to the cytotoxicity of benzo[a]pyrene. However, preexposure of the keratinocytes to Arochlor did not increase their sensitivity to benzo[a]pyrene. Neither the keratinocytes, fibroblasts, nor HepG2 cells were sensitive to acenaphthene. Addition of hamster or rat hepatic S9 mix, however, resulted in toxicity from benzo[a]pyrene and acenaphthene. 7,12-Dimethylbenz[a]anthracene was only mildly cytotoxic to the fibroblasts, and its cytotoxicity was not enhanced in the presence of rat or hamster S9 mix. Exposure of the HepG2 cells to 7,12-dimethylbenz[a]anthracene showed progressive toxicity over a 1- to 3-d period. Prior exposure of the HepG2 cells to Arochlor did not enhance their sensitivity to 7,12-dimethylbenz[a]anthracene. Human keratinocytes were sensitive to 7,12-dimethylbenz[a]anthracene, with cytotoxicity markedly increasing over a 1- to 3-d period.
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PMID:Mediating role of metabolic activation in in vitro cytotoxicity assays. 315 1

In the Reuber (H35) hepatoma cell strain, microsomal aryl hydrocarbon (benzo[a]pyrene) hydroxylase is induced 25-fold by the polycyclic hydrocarbon benz[a]anthracene but is not induced by the steroid hormone dexamethasone. Soluble tyrosine aminotransferase is induced sixfold by dexamethasone and twofold by benz[a]anthracene. Each enzyme requires similar inducer concentrations for induction, and their induction kinetics are similar. The induction of each enzyme requires RNA and protein synthesis; in each case the transcriptional and translational steps can occur independently. The two induction systems are differentially sensitive to inhibitors of macromolecular synthesis. Simultaneous exposure to both inducers produces increases in both enzyme activities that are greater than those produced by either inducer alone. Each inducer acts at a pretranslational level to produce this synergistic effect. The results suggest that the requirements for macromolecular synthesis are similar for the induction of each enzyme, but that the turnover of enzyme-specific macromolecules may differ for each.
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PMID:Induction of aryl hydrocarbon (benzo(a)pyrene) hydroxylase and tyrosine aminotransferase in hepatoma cells in culture. 415 58

Aryl hydrocarbon hydroxylase activity is inducible in mouse 3T3 fibroblasts by benz[alpha]anthracene, whereas no detectable basal or inducible levels of this enzyme occur in rat-hepatoma tissue culture cells. Conversely, tyrosine aminotransferase activity is inducible in hepatoma cells by dexamethasone, whereas only low noninducible levels of this enzyme exist in 3T3 cells. In hybrids formed by fusion of these two parent lines, levels of inducible hydroxylase activity range from the same as, to more than 20-fold greater than, that in the 3T3 parent; aminotransferase levels remain very low and noninducible in all of these same hybrids. A majority of the 1S-chromosomal complement from each parent is retained in most of these hybrids. The kinetics of hydroxylase induction and degradation, responses of hydroxylase induction to actinomycin D and cycloheximide, and the relative thermolability of the control and induced activities are similar in the 3T3 parent and in the hybrids. Failure to inactivate any of the aminotransferase activity in the hybrids with antibody specific for the rat enzyme indicates that all of the basal noninducible aminotransferase activity is derived from the mouse 3T3 parent.
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PMID:Expression of aryl hydrocarbon hydroxylase induction and suppression of tyrosine aminotransferase induction in somatic-cell hybrids. 440 6


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