UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcripts of the murine CYP1A1 (cytochrome P1450) mRNA are markedly elevated in mutant hepatoma cell lines that contain missense mutations in the Cyp1a-1 structural gene. This putative derepression extends to other genes in the [Ah] battery. To test whether the Cyp1a-1 gene product is involved in a mechanism of feedback regulation of transcription, we introduced expression plasmids carrying the murine wild-type Cyp1a-1 cDNA into the mutant hepatoma cells. Measurements of steady-state mRNA levels and of transcriptional rates in the transfectants reveal that expression of a functional, exogenous CYP1A1 protein is sufficient to restore the repression of the endogenous gene, as well as restore the inducibility by dioxin, and that this effect takes place primarily at the level of transcription. Similar experiments with expression plasmids that carry the human CYP1A2 cDNA indicate that the CYP1A2 protein (cytochrome P3450) can also function as a transcriptional repressor. In addition, we find that expression of the Nmo-1 [NAD(P)H:menadione oxidoreductase] gene, a third member of the [Ah] gene battery, is also repressed by the exogenous expression of either Cyp1a-1 or CYP1A2 cDNA. These results indicate that the gene product of either member of the mammalian CYP1 family has a previously unrecognized transcriptional regulatory function, which is likely to be exerted by modification of preexisting trans-acting factors. This function may help bring about a fast reprogramming of gene expression, as might be needed during detoxification of toxic foreign chemicals.
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PMID:The murine Cyp1a-1 gene negatively regulates its own transcription and that of other members of the aromatic hydrocarbon-responsive [Ah] gene battery. 208 80

Treatment of rat hepatoma H-4-II E cells with alpha-naphthoflavone (alpha NF) (10(-8), 10(-7), 10(-6)M) resulted in only minimum induction of ethoxyresorufin O-deethylase (EROD) activity and cytochrome P4501A1 mRNA levels only at 10(-6)M. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) caused maximum or near maximum induction responses at 10(-8) and 10(-9)M. In a time-course study with TCDD (10(-9)M), and TCDD plus alpha NF (cotreated), alpha NF significantly inhibited the induction of EROD activity and cytochrome P4501A1 mRNA levels by TCDD for 6-24 h after initial exposure of the cells to the chemicals. In addition, treatment of the cells with 10(-9)M TCDD in the presence or absence of 10(-8), 10(-7), and 10(-9)M alpha NF showed that the latter compound inhibited the induction effects by TCDD in a concentration-dependent manner and these inhibitory effects could be overcome, in part, by a higher concentration of TCDD (10(-8)M). Treatment of the rat hepatoma H-4-II E cells with [3H]TCDD showed that within 60 min, there was an initial rapid increase in nuclear [3H]TCDD receptor complex levels (38 fmol/mg protein) which decreased to less than 10 fmol/mg protein within 4 h and remained relatively constant for up to 24 h. However, in cells treated with [3H]TCDD (10(-9)M) plus alpha NF (10(-6)M) the levels of the nuclear [3H]TCDD receptor complex were less than 5 fmol/mg protein throughout the 24-h time course. These data, coupled with the results which indicate that the alpha NF competitively inhibits the binding of [3H]-TCDD to the cytosolic aryl hydrocarbon (Ah) receptor, suggest that alpha NF inhibits the TCDD-mediated induction of CYP1A1 gene transcription and translation by direct competition for cytosolic Ah receptor binding sites.
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PMID:The mechanism of action of alpha-naphthoflavone as an inhibitor of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced CYP1A1 gene expression. 216 79

Three nuclear factors, the Ah receptor, XF1, and XF2, bind sequence specifically to the Ah response elements or xenobiotic response elements (XREs) of the cytochrome P450IA1 (P450c) gene. The interactions of these factors with the Ah response element XRE1 were compared by three independent methods, methylation interference footprinting, orthophenanthroline-Cu+ footprinting, and mobility shift competition experiments, using a series of synthetic oligonucleotides with systematic alterations in the XRE core sequence. These studies established the following (i) all three factors interact sequence specifically with the core sequence of XRE1; (ii) the pattern of contacts made with this sequence by the Ah receptor are different from those made by XF1 and XF2; and (iii) although XF1 and XF2 can be distinguished by the mobility shift assay, the sequence specificities of their interactions with XRE1 are indistinguishable. Further characterization revealed the following additional differences among these three factors: (i) XF1 and XF2 could be extracted from nuclei under conditions quite different from those required for extraction of the Ah receptor; (ii) XF1 and XF2 were present in the nuclei of untreated cells and did not respond to polycyclic compounds, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and beta-napthoflavone, while nuclear Ah receptor was undetectable in untreated cells and rapidly increased in response to TCDD; (iii) inhibition of protein synthesis did not affect the TCDD-induced appearance of the Ah receptor but substantially decreased the constitutive activities of XF1 and XF2, suggesting that the Ah receptor must be present in untreated cells in an inactive form that can be rapidly activated by polycyclic compounds, while the constitutive expression of XF1 and XF2 depends on the continued synthesis of a relatively unstable protein; (iv) the receptor-deficient and nuclear translocation-defective mutants of the hepatoma cell line Hepa1, which are known to lack nuclear Ah receptor, expressed normal levels of XF1 and XF2, suggesting that the former factor is genetically distinct from the latter two; and (v) a divalent metal ion, probably Zn2+, is known to be an essential cofactor for the Ah receptor but was not required for the DNA-binding activities of XF1 and XF2. Together, these findings indicate that the Ah receptor is distinct from XF1 and XF2, while the latter two activities may be related. Because the DNA-binding domains of these three factors overlap substantially, their binding to XREs is probably mutually exclusive, which suggests that the interplay of these factors at Ah response elements may be important to the regulation of CYP1A1 gene transcription. The results of preliminary transfection experiments with constructs harboring XREs upstream of the chloramphenicol acetyltransferase gene driven by a minimal simian virus 40 promoter are presented that are consistent with this hypothesis.
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PMID:Multiple DNA-binding factors interact with overlapping specificities at the aryl hydrocarbon response element of the cytochrome P450IA1 gene. 217 7

In mouse hepatoma cells, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the transcription rate of the CYP1A1 gene, which encodes a cytochrome P-450 enzyme. In this study, we analyzed the DNA region immediately upstream of the CYP1A1 gene. A domain that extends upstream to nucleotide--166 was found to function as a transcriptional promoter. The promoter was silent when uncoupled from the dioxin-responsive enhancer located farther upstream. DNase footprinting experiments indicated that nuclear proteins interact with distinct domains of the promoter in a TCDD-independent fashion. Mutational analyses indicated that the CYP1A1 promoter contains at least three functional domains, including a TATAAA sequence, a CCAAT box transcription factor/nuclear factor I-like recognition motif, and a guanine-rich G box.
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PMID:Functional analysis of the transcriptional promoter for the CYP1A1 gene. 239 86

The mouse cytochrome P1450 (CYP1A1) gene is responsible for the metabolism of numerous carcinogens and toxic chemicals. Induction by the environmental contaminant tetrachlorodibenzo-p-dioxin (TCDD) requires a functional aromatic hydrocarbon (Ah) receptor. We examined the 5'-flanking region of the CYP1A1 gene in mouse hepatoma Hepa-1 wild-type cells and a mutant line having a defect in chromatin binding of the TCDD-receptor complex. We identified two cis-acting elements (distal, -1071 to -901 region; proximal, -245 to -50 region) required for constitutive and TCDD-inducible CYP1A1 gene expression. Three classes of DNA-protein complexes binding to the distal element were identified: class I, found only in the presence of TCDD and a functional Ah receptor, that was heat labile and not competed against by simian virus 40 (SV40) early promoter DNA; class II, consisting of at least three constitutive complexes that were heat stable and bound to SV40 DNA; and class III, composed of at least three constitutive complexes that were thermolabile and were not competed against by SV40 DNA. Essential contacts for these proteins were centered at -993 to -990 for the class I complex, -987, -986, or both for the class II complexes, and -938 to -927 for the class III complexes. The proximal element was absolutely essential for both constitutive and TCDD-inducible CYP1A1 gene expression, and at least two constitutive complexes bound to this region. These data are consistent with the proximal element that binds proteins being necessary but not sufficient for inducible gene expression; interaction of these proteins with those at the distal element was found to be required for full CYP1A1 induction by TCDD.
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PMID:Regulation of mouse CYP1A1 gene expression by dioxin: requirement of two cis-acting elements during induction. 254 80

Enzyme-inducing and cytotoxic effects of South African bedding materials were investigated using a mouse hepatoma cell line, Hepa-1, cell culture system. This cell culture system is a convenient and sensitive method for the screening of bedding materials for the presence of compounds that could be potentially harmful to animals and thus the experimental outcome. Cells were exposed to acetone extracts of the different materials or their components. Corn cobs displayed very little or no CYP1A1-inducing or cytotoxic effects, whilst vermiculite and unbleached pulp from pine and eucalyptus showed greater induction and cytotoxic properties. The latter properties were lower than those produced by the different recycled paper extracts. Pine shavings (Pinus elliottii) and the different wood components making up industrial sawdust expressed the highest cytotoxic and CYP1A1-inducing properties.
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PMID:The in vitro enzyme-inducing and cytotoxic properties of South African laboratory animal contact bedding and nesting materials. 760 2

We have studied the effect of several environmental chemicals on the transient expression of a chloramphenicol acetyltransferase (cat) reporter gene linked to the promoter sequences in the long terminal repeat (LTR) of the human immunodeficiency virus type 1 (HIV-1). Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1 cells. The induction of CAT after TCDD treatment is abolished by administration of N-acetyl-L-cysteine or 2-mercaptoethanol and does not take place in a mutant cell line that lacks CYP1A1 enzymatic activity. Linker-scanning mutational analysis of transcription factor binding sites in the promoter revealed that both the NF kappa B and an adjacent aromatic hydrocarbon response element (AhRE) are required for TCDD-dependent CAT expression. In addition, mutation of the NFAT/AP-1 binding sites in the negative regulatory region of the promoter increases the magnitude of the TCDD effect. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases infectious HIV-1 titers in experimental systems and for epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke, is associated with an acceleration in AIDS progression.
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PMID:Dioxin activates HIV-1 gene expression by an oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. 760 37

The promutagenic and procarcinogenic heterocyclic amines (HAs) found in cooked meats are N-hydroxylated by microsomal cytochrome P450 enzymes as the first step in their metabolic activation. In cynomolgus monkeys, one of the HAs, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), has been shown to be a potent hepatocarcinogen. However, the structurally similar HA 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) lacks this potency to induce hepatocellular carcinoma in monkeys. Liver microsomes from cynomolgus monkeys show a striking substrate specificity for the metabolic activation of IQ and MeIQx, the former being a far better substrate for N-hydroxylation. Western blot analysis showed that cynomolgus monkey hepatic microsomes constitutively express P450s immunologically related to the human CYP3A, CYP2C, and low levels of CYP1A1. For comparison, Western blot analysis of rat, human and patas monkey microsomes was also carried out. Treatment of cynomolgus monkeys with rifampicin induced hepatic cytochromes P450 related to human CYP3A4 and CYP2C9/10 without inducing CYP1A1 or CYP1A2. Immunoblot analysis also showed that chronic exposure of cynomolgus monkeys to IQ induced hepatic microsomal cytochrome CYP1A1 and CYP1A2, similarly but lesser in magnitude to that observed with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCCD) induction. Using the Ames Salmonella mutagenicity assay, we examined the effect of the inducers on the mutagenic activation (i.e. N-hydroxylation) of IQ and MeIQx by cynomolgus monkey hepatic microsomes. We also examined the mutagenic activation of these HAs by rat, human and patas monkey liver microsomes. Microsomes from cynomolgus monkeys treated with rifampicin showed a 3-fold increase in the mutagenic activation of IQ but showed no increase in the mutagenic activation of MeIQx. Since cytochromes P4503A and/or P4502C are constitutively expressed in cynomolgus monkey hepatic microsomes, and upon induction with rifampicin are associated with an increased metabolic activation of IQ but not MeIQx, it appears that CYP3A and/or CYP2C are the isoform(s) showing the selective substrate specificity in the metabolic activation of IQ over MeIQx. Treatment of monkeys with TCDD significantly increased the mutagenic activation of both IQ and MeIQx, concomitant with an induction of CYP1A isozymes. Thus, it appears that TCDD-inducible CYP1A enzymes N-hydroxylate both substrates without selectivity. Together, these findings suggest that CYP3A and CYP2C are the principal isoforms in the cynomolgus monkey, associated with the metabolic activation implicated in the induction of hepatocarcinogenicity by IQ. Furthermore, the poor metabolic activation of MeIQx by CYP3A and CYP2C, coupled with low constitutive levels of CYP1A isozymes, provide a metabolic explanation for the low hepatocarcinogenic potency of MeIQx in cynomolgus monkeys.
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PMID:Cytochromes P450 in cynomolgus monkeys mutagenically activate 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) but not 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx). 761 88

Rat hepatoma H4IIE and mouse hepatoma Hepa 1c1c7 cells were transiently transfected with a plasmid construct that contained the bacterial chloramphenicol acetyltransferase (CAT) gene under the control of the mouse mammary tumor virus promoter and one copy of the dioxin responsive element. Treatment of transfected H4IIE and Hepa 1c1c7 cells with 10(-13) to 10(-6) M 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a concentration-dependent increase in transient CAT activity. Maximum CAT activity was induced in both cell lines by exposure to 10(-9) M TCDD. The induction of CAT activity correlated well with the TCDD-induced, P4501A1-dependent ethoxyresorufin O-deethylase activity. Cotreatment of transfected cells with 10(-9) M TCDD and 10(-8) to 10(-6) M alpha-naphthoflavone (alpha NF) or 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) resulted in a concentration-dependent reduction of TCDD-induced CAT activity. Treatment of cells with 10(-6) M alpha NF or MCDF alone resulted in only minimal induction of CAT activity. Both antagonists inhibited the induction of genes under the control of the CYP1A1 and mouse mammary tumor virus promoters, which indicates that the alpha NF- and MCDF-mediated antagonism of TCDD-induced, aryl hydrocarbon receptor-dependent gene transcription does not depend on promoter context.
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PMID:In vitro inhibition of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced activity by alpha-naphthoflavone and 6-methyl-1,3,8-trichlorodibenzofuran using an aryl hydrocarbon (Ah)-responsive construct. 766 69

Benzo[a]pyrene (BaP) can be metabolically activated to an ultimate carcinogen, (+)-anti-BaP-7,8-dihydrodiol-9,10-epoxide [(+)-anti-BaPDE] by cells in culture. This activation involves oxidation by specific isoforms of cytochrome P450s such as CYP1A1. The human hepatoma cell line, HepG2, was used to examine the effect of inhibition of CYP1A1 activity by anti CYP1A1 specific antibodies on BaP metabolism. Metabolism of BaP to water-soluble metabolites by HepG2 cells in culture was 50% lower in fluorescein isothiocyanate (FITC)-insulin-CYP1A1-antibody-conjugate-treated cells than in control cells. However, FITC-insulin (lacking anti CYP1A1 conjugates) or insulin alone also decreased BaP metabolism by 50%. This insulin-induced inhibition of BaP metabolism was observed for cultures treated with a concentration range of FITC-insulin from 50-1000 nM. FITC-conjugated gamma-globulin showed no significant binding to HepG2 cells by fluorescence microscopy, however, FITC-insulin-antibody conjugates bound extensively, suggesting that FITC-insulin conjugates still retain the ability to bind insulin receptors. These results demonstrate that free insulin, FITC-insulin or FITC-insulin conjugated to antibodies are effective inhibitors of BaP metabolism in cells in culture.
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PMID:Inhibition of benzo[a]pyrene metabolism by insulin, FITC-insulin and an FITC-insulin-antibody conjugate in the human hepatoma cell line HepG2. 767 46

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