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)

Hepa-1c1c7, a mouse hepatoma cell line, was used to study the effect of cytochrome P1-450 inducers on the binding of 125I-epidermal growth factor (EGF), 125I-insulin, or [20-3H]phorbol 12,13-dibutyrate each to its specific cell-surface receptor. After a 24-h exposure to the cultured cells, several polycyclic hydrocarbon P1-450 inducers decrease the binding of EGF to EGF receptors much more than phenobarbital does. There appears to be a selectivity in the inhibitory effects: whereas EGF binding to EGF receptors is blocked, the binding of either phorbol ester or insulin each to its specific cell-surface receptors remains unaffected. The rank order of binding affinities of these chemicals to the cytosolic Ah receptor (2,3,7,8-tetrachlorodibenzo-p-dioxin much greater than benzo[a]pyrene greater than benzo[a]anthracene greater than 6-aminochrysene much greater than phenobarbital) is not correlated with their effects on EGF binding capacity. The effect of polycyclic hydrocarbons on EGF binding takes 24 h at 37 degrees C to be maximal, whereas phorbol 12-myristate 13-acetate, a potent tumor-promoting compound, inhibits EGF binding in less than 30 min. Removal of benzo[a]anthracene from the growth medium after 24 h results in a gradual recovery in EGF binding, indicating that the effect is reversible. Benzo[a]pyrene and benzo[a]anthracene are relatively ineffective at decreasing EGF binding to the EGF receptors in Hepa-1 mutant clones c2 and c4, which lack a normally functioning Ah receptor and inducible aryl hydrocarbon hydroxylase activity (P1-450). The very toxic metabolite (+)-7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene, when added directly to the growth medium of c4 cells, however, is effective at decreasing EGF binding. These data suggest that electrophilic metabolites of polycyclic aromatic compounds, formed by P1-450 induced during the exposure of Hepa-1 cells to these chemicals, are important in decreasing EGF binding to the EGF cell-surface receptor. Occupancy of the Ah receptor per se does not affect EGF binding.
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PMID:Effects of cytochrome P1-450 inducers on the cell-surface receptors for epidermal growth factor, phorbol 12,13-dibutyrate, or insulin of cultured mouse hepatoma cells. 630 1

The biologic and toxic effects of polychlorinated biphenyls (PCBs) are remarkably dependent on their structure. The most toxic PCBs, namely 3,3',4,4'-tetra-, 3,3',4,4',5-penta- and 3,3',4,4',5,5'-hexachlorobiphenyl are substituted in at least one meta and para position on both phenyl rings (i.e., the lateral positions) and contain no ortho-chloro substituents. These three congeners and a fourth PCB, namely 3,4,4',5-tetrachlorobiphenyl, are approximate isostereomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and, in common with TCDD, induce hepatic microsomal benzo[a]pyrene or aryl hydrocarbon hydroxylase (AHH) in rats and rat hepatoma cells in culture. The mono-ortho substituted analogs of the four laterally substituted PCBs also induce microsomal AHH activity and simultaneously enhance microsomal enzyme activities which are inducible by phenobarbitone (PB). This group of PCBs exhibits many of the properties of 2,3,7,8-TCDD and related polychlorinated dibenzo-p-dioxins; there is a close parallel in the relative potencies of these PCBs for AHH induction and their binding affinities for the Ah receptor protein and some of these PCBs are also toxic. Preliminary studies on other halogenated biphenyls confirm that the polarizability of a lateral substituent is an important factor in their activity as AHH inducers (i.e., I greater than Br greater than Cl greater than F). However, preliminary results with other substituted halogenated biphenyls suggest that additional structural factors are also important in determining the activity of these compounds.
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PMID:Halogenated biphenyls: molecular toxicology. 681 34

The capacity of 19 polycyclic aromatic compounds and 15 benzo[a]pyrene metabolites to displace [1,6-3H]2,3,7,8-tetrachlorodibenzo-p-dioxine ([3H]TCDD) from the mouse liver cytosolic Ah receptor was examined. We compared our data with various parameters taken from previously published results: the capacity of seven polycyclic hydrocarbons to induce aryl hydrocarbon hydroxylase (AHH) activity in human cell cultures, the capacity of 10 polycyclic hydrocarbons to induce azo dye N-demethylase activity in rat liver, the capacity of 6 polycyclic hydrocarbons to shorten zoxazolamine paralysis times in the intact rat, and the capacity of 15 benzo[a]pyrene metabolites to induce AHH activity in rat hepatoma H-4-II-E cultures. An excellent correlation is seen between the capacity to displace the radioligand from the Ah receptor and the capacity to induce these monooxygenase activities. differences in the rate of cellular uptake and formation of alkali-extractable metabolites of dibenzo[a,h]anthracene, 3-methylcholanthrene, and benzo[a]anthracene in Hepa-1 mouse hepatoma cell cultures do not account for differences in the capacity of these three polycyclic hydrocarbons to displace [3H]TCDD from the Ah receptor.
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PMID:The Ah regulatory gene product. Survey of nineteen polycyclic aromatic compounds' and fifteen benzo[a]pyrene metabolites' capacity to bind to the cytosolic receptor. 708 63

4'-Iodo-, 4'-bromo-, 4'-chloro- and 4'-fluoro-2,3,4,5-tetrachlorobiphenyl were administered to immature male Wistar rats and the effects of this homologous series of 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal drug-metabolizing enzymes were determined. All the halogenated biphenyls increased microsomal benzo[a]pyrene hydroxylase (or aryl hydrocarbon hydroxylase, AHH), ethoxyresorufin (ER) O-deethylase and dimethylaminoantipyrine (DMAP) N-demethylase. The effects of the 4'-halo-2,3,4,5-tetrachlorobiphenyls on the microsomal enzyme activities and on the relative peak intensities and spectral shifts of the reduced cytochrome P-450:CO and ethylisocyanide (EIC) binding difference spectra were similar to those observed after coadministration of phenobarbitone (PB) and 3-methylcholanthrene (MC). The relative activities of the halogenated biphenyls were determined using two in vitro assays; namely cytochrome P-448 associated induction in rat hepatoma H-4-II E cells in culture and competitive binding to the hepatic cytosolic Ah receptor protein from male Wistar rats. Dose-response experiments for the iodo, bromo, chloro and fluoro analogs gave EC50(M) values of 8.5 x 10(-9), 6.6 x 10(-8), 5.7 x 10(-7), and 3.3 x 10(-5), and 1.5 x 10(-6), 2.5 x 10(-6), 4.1 x 10(-6) and 2.5 x 10(-5) for the Er O-deethylase induction and receptor binding assays respectively. The relative potencies of the 4'-halo-2,3,4,5-tetrachlorobiphenyls followed the order I greater than Br greater than Cl greater than F for both assays and differences in the EC50 values for the iodo and fluoro analogs were greater than three orders of magnitude for ER O-deethylase induction in rat hepatoma cells in culture. One possible explanation for these effects may be associated with differences in the polarizability of the laterally substituted halogen groups. However, other differences in the physico-chemical properties of the halogen atoms may also be important.
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PMID:Halogenated biphenyls as AHH inducers: effects of different halogen substituents. 713 65

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells. 757 30

We have cloned and sequenced the mouse NMO1 cDNA, which encodes the NAD(P)H:menadione oxidoreductase [also called NAD(P)H:(quinone acceptor) oxidoreductase; quinone reductase; azo dye reductase; DT diaphorase; EC 1.6.99.2]. The cDNA is 1528 bp in length excluding the poly(A+) tail, and has 5' and 3' nontranslated regions of 108 bp and 595 bp, respectively. The deduced protein contains 274 amino acids, including the first methionine (M(r) = 30,959). The mouse NMO1 protein is: 94% similar to the rat NMO1 and 86.5% to the human NMO1 proteins; 49.3% identical to the human NQO2 protein; and < 20% similar to several dozen other proteins in the quinone oxidoreductase superfamily. Southern hybridization analysis of mouse DNA reveals that the Nmo1 gene is likely to span less than a total of 20 kb. The Nmo1 gene is highly inducible by 2,3,7,8,-tetrachlorodibenzo-p-dioxin (dioxin; TCDD) in mouse liver and mouse cell cultures. TCDD inducibility of NMO1 is detectable at 12 and 18 days of gestation, but markedly elevated at 1-3 weeks post partum as compared with the 6- and 12-week-old mouse. NMO1 mRNA levels are strikingly elevated in the untreated mouse hepatoma Hepa-1c1c7 mutant line c37 lacking CYP1A1 (aryl hydrocarbon hydroxylase) activity, and in the untreated 14CoS/14CoS mouse cell line having an 'oxidative stress response' caused by homozygous deletion of about 3800 kb on chromosome 7. Previous work and the data in this report show that the murine Nmo1 gene is regulated by three distinct mechanisms: CYP1A1 metabolism-dependent repression, Ah receptor-mediated induction by TCDD, and activation by the chromosome 7-mediated oxidative stress response.
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PMID:Mouse dioxin-inducible NAD(P)H: menadione oxidoreductase: NMO1 cDNA sequence and genetic differences in mRNA levels. 770 40

In mouse hepatoma cells, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin) induces Cyp1A1 gene transcription, a process that requires two basic helix-loop-helix regulatory proteins, the aromatic hydrocarbon receptor (AhR) and the aromatic hydrocarbon receptor nuclear translocator (Arnt). We have used a ligation-mediated PCR technique to analyze dioxin-induced changes in protein-DNA interactions and chromatin structure of the Cyp1A1 enhancer-promoter in its native chromosomal setting. Dioxin-induced binding of the AhR/Arnt heteromer to enhancer chromatin is associated with a localized (about 200 bp) alteration in chromatin structure that is manifested by increased accessibility of the DNA; these changes probably reflect direct disruption of a nucleosome by AhR/Arnt. Dioxin induces analogous AhR/Arnt-dependent changes in chromatin structure and accessibility at the Cyp1A1 promoter. However, the changes at the promoter must occur by a different, more indirect mechanism, because they are induced from a distance and do not reflect a local effect of AhR/Arnt binding. Dose-response experiments indicate that the changes in chromatin structure at the enhancer and promoter are graded and mirror the graded induction of Cyp1A1 transcription by dioxin. We discuss these results in terms of a TCDD-induced shift in an equilibrium between nucleosomal and nonnucleosomal chromatin configurations.
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PMID:Dioxin induces localized, graded changes in chromatin structure: implications for Cyp1A1 gene transcription. 779 78

The mouse hepatoma cell line Hepa-1 is inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for both CYP1A1 (aryl hydrocarbon hydroxylase, AHH) and class 3 aldehyde dehydrogenase (ALDH3) enzymes. To test the hypothesis of a common regulatory mechanism, several AHH deficient mutants of Hepa-1 were studied for their ALDH3 activities and specific mRNA levels before and after TCDD treatment. The recessive (with respect to the wild-type Hepa-1) mutants have defects in Cypla-1 structural gene (mutant c1) or in the Ah (aryl hydrocarbon) receptor (mutants c2 and c6 with decreased levels of Ah receptor; mutant c4 defective in the DNA binding of the Ah receptor). The results with these mutants suggested that Ah receptor nuclear translocator protein, ARNT, is needed for ALDH3 expression. Two dominant mutants, one of which is characterized by preventing the binding of the Ah receptor complex to DNA, were also studied. Surprisingly, these mutants possessed elevated levels of ALDH3 mRNA and enzyme activities which were also inducible by TCDD. The binding of Ah receptor-ligand complex to DNA was thus not needed for the expression of ALDH3. A dominant repressor for Cypla-1 gene transcription did not prevent the derepression or induction of ALDH3. The results thus suggest that Aldh-3 gene is regulated by a mechanism independent of the Ah receptor.
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PMID:Comparison of expression of aldehyde dehydrogenase 3 and CYP1A1 in dominant and recessive aryl hydrocarbon hydroxylase-deficient mutant mouse hepatoma cells. 782 19

The exposure of two hepatoma cell lines, Hep G2 and Hepa-1, to moderate hydrodynamic shear, in microcarrier-attached suspension cultures, resulted in the transient induction of cytochrome P450IA1 (CYP1A1). Both cell lines have been characterized with respect to their Ah receptor (AhR) concentrations and induce CYP1A1 in response to exposure to xenobiotics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Using an AhR antagonist, alpha-naphthoflavone (alpha-NF) and a protein kinase C (PKC) inhibitor, staurosporine (ST), in the Hep G2 cell line, the induced CYP1A1 activity was modulated in the same manner as when the cells were coexposed to TCDD and either alpha-NF or ST. Exposure of the Hep G2 cell line to TCDD and shear resulted in both enhancement of the induced CYP1A1 activity in addition to a competitive response. Finally, using the wild type and AhR defective Hepa-1 cell lines, it was demonstrated that a functional AhR was required for shear-induced CYP1A1 expression. The data obtained in the three cell lines indicate a role for the AhR in the induction of CYP1A1 by shear in agitated microcarrier cultures.
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PMID:Possible involvement of the Ah receptor in the induction of cytochrome P-450IA1 under conditions of hydrodynamic shear in microcarrier-attached hepatoma cell lines. 788 22

Cytochrome P4501A1 and its associated aryl hydrocarbon hydroxylase activity are highly inducible in the mouse hepatoma cell line, Hepa-1, by substrates of the enzyme and related compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mutants of this cell line, deficient in P4501A1 inducibility, were isolated. Some of the mutants show a dominant phenotype. Such mutants may have resulted from a genetic alteration leading to the inappropriate activation of a repressor gene that normally functions to restrict high level inducibility to the liver and certain other organs or to certain developmental stages. One dominant mutant was shown to express a protein that prevents binding of the liganded aryl hydrocarbon (Ah) receptor (which mediates induction of P4501A1) to its recognition sequence in DNA (the xenobiotic responsive element, or XRE). The majority of mutants are recessive, and were assigned to four different complementation groups (which probably correspond to four different genes). Gene A corresponds to the structural gene (Cyp1a-1) for P4501A1. Mutations in genes B, C and D all affect functioning of the Ah receptor. A cDNA for gene C was cloned. The encoded protein (ARNT) is required for ligand-dependent translocation of the Ah receptor to the nucleus and its binding to the XRE. ARNT and the Ah receptor form a heterodimeric complex which binds the XRE in a fashion such that both subunits bind the XRE directly. Both ARNT and the Ah receptor contain basic helix-loop-helix motifs. Such motifs have been identified in several transcription factors that bind DNA as heterodimers or homodimers. The roles of the proteins corresponding to the B and D genes are presently under investigation.
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PMID:A genetic analysis of processes regulating cytochrome P4501A1 expression. 794 73


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