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1.
Bull Exp Biol Med ; 158(6): 789-93, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25894779

RESUMO

PT/Y mice used for studies of the effects of mutagens are characterized by the absence of spontaneous tumors of the liver, but often develop these tumors in response to chronic oaminoazotoluene treatment. The level of glucocorticoid induction of adaptive hepatic enzyme tyrosine aminotransferase decreases by more than 70% 24 h after acute injection of o-aminoazotoluene to these animals. These mice can serve as a model for studies of the relationship between the effect of carcinogens on the regulation of activity of adaptive hepatic enzymes and their capacity to induce the development of liver tumors.


Assuntos
Glucocorticoides/farmacologia , Fígado/metabolismo , Tirosina Transaminase/metabolismo , o-Aminoazotolueno/toxicidade , Animais , Camundongos
2.
Bull Exp Biol Med ; 157(3): 368-70, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25065317

RESUMO

The effects of ortho-aminoazotoluene on carcinogenic activity of diethylnitrosamine were studied in CBA and ICR mice. Injection of ortho-aminoazotoluene before and after diethylnitrosamine led to a significant reduction of its anticarcinogenic effect, judging from significantly lower level of liver tumors. Pentachlorophenol, inhibitor of sulfotransferase (catalyzing the terminal stage of ortho-aminoazotoluene metabolic activity), stimulated its carcinogenic effect on mouse liver. On the other hand, pentachlorophenol reduced the protective effect of ortho-aminoazotoluene on diethylnitrosamine-induced hepatocarcinogenesis in mice. Presumably, the carcinogenic and anticarcinogenic effects of ortho-aminoazotoluene were realized by its initial form or intermediate (non-sulfated) metabolites.


Assuntos
Anticarcinógenos/farmacologia , Carcinogênese/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/metabolismo , o-Aminoazotolueno/farmacologia , Animais , Dietilnitrosamina , Feminino , Fígado/química , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Camundongos Endogâmicos CBA , Camundongos Endogâmicos ICR , Pentaclorofenol/farmacologia , Sulfotransferases/antagonistas & inibidores , Sulfotransferases/metabolismo
3.
Biofizika ; 59(4): 776-84, 2014.
Artigo em Russo | MEDLINE | ID: mdl-25707246

RESUMO

The modifying effect of the one compound on carcinogenicity of the other in the combined application is attributed usually to some changes in the carcinogen metabolism, i.e. its activation or inactivation. In this paper, when used separately, diethylnitrosamine (DENA) induced 4-6 times more neoplastic lesions in the liver of suckling mice than ortho-aminoazotoluene (OAT) did. However, after combined treatment with both carcinogens the total number of hepatic lesions was significantly lower than that in mice treated with DENA only. Similar effect was observed when OAT was administered 3 days before or 3 days after DENA injection. The observed protective effect is not mediated at metabolic level, because OAT has no effect on metabolism of DENA in mouse liver. Our findings can be unequivocally explained by the competition of the carcinogens for target protein molecules, presumably transcription factors, participating in hepatocyte differentiation, which differently interact with and are diversely impaired by different compounds.


Assuntos
Carcinógenos/farmacologia , Dietilnitrosamina/efeitos adversos , Neoplasias Hepáticas Experimentais , Proteínas de Neoplasias/metabolismo , o-Aminoazotolueno/efeitos adversos , Alquilantes/efeitos adversos , Alquilantes/farmacologia , Animais , Animais Recém-Nascidos , Corantes/efeitos adversos , Corantes/farmacologia , Dietilnitrosamina/farmacologia , Antagonismo de Drogas , Feminino , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos ICR , o-Aminoazotolueno/farmacologia
4.
Biofizika ; 59(3): 527-32, 2014.
Artigo em Russo | MEDLINE | ID: mdl-25715596

RESUMO

It is found that after administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB,) which was hepatocarcinogenic to rats, in suckling mice, the number of neoplastic lesions in the liver of mice was 3 times higher than after analogous administration of equimolar dose of ortho-aminoazotoluene (OAT)). However, in the Ames test (TA-98 strain of Salmonella typhimurium) with activation by hepatic enzymes (S-9 fraction) of both intact and Aroclor-1254-induced mice and rats OAT contributed by an order of magnitude to revertant colonies compared to 3'-Me-DAB. In vivo inhibition of sulfotransferase activity, the enzyme which catalyzes the final stage of the mutagenic activation of aminoazo dyes, had no effect on carcinogenicity of 3'-Me-DAB but more than 4 times elevated that of OAT. It was concluded that the mechanism of carcinogenic action of aminoazo dyes studied is not genotoxic and that the carcinogenic potential of OAT is lost in the process of mutagenic activation.


Assuntos
Carcinógenos/toxicidade , Corantes/toxicidade , Neoplasias Hepáticas Experimentais , Metildimetilaminoazobenzeno/toxicidade , Mutagênicos/toxicidade , o-Aminoazotolueno/toxicidade , Animais , Carcinógenos/farmacologia , Corantes/farmacologia , Fígado/enzimologia , Fígado/patologia , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Metildimetilaminoazobenzeno/farmacologia , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos ICR , Mutagênicos/farmacologia , Ratos , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , o-Aminoazotolueno/farmacologia
5.
Bull Exp Biol Med ; 154(5): 664-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23658894

RESUMO

Pentachlorophenol (aromatic amine and azo stain metabolic stimulation inhibitor) reduced the hepatocarcinogenic activity of 4-aminoazobenzene and reduced that of ortho-aminoazotoluene in suckling mice. Both 4-aminoazobenzene and ortho-aminoazotoluene exhibited mutagenic activity in Ames' test in vitro on S. typhimurium TA 98 strain with activation with liver enzymes; this mutagenic activity was similarly suppressed by adding pentachlorophenol into activation medium. Induction of xenobiotic metabolism enzymes, stimulating the mutagenic activity of ortho-aminoazotoluene, suppressed its carcinogenic effect on mouse liver. Hence, ortho-aminotoluene (the initial compound), but not its mutagenic metabolites, was the direct active hepatocarcinogen for mice.


Assuntos
Carcinogênese , Carcinógenos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pentaclorofenol/farmacologia , o-Aminoazotolueno/metabolismo , Animais , Testes de Carcinogenicidade , Carcinógenos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos ICR , Testes de Mutagenicidade , Pentaclorofenol/química , Pentaclorofenol/metabolismo , o-Aminoazotolueno/química , o-Aminoazotolueno/toxicidade
6.
Cell Cycle ; 12(2): 353-64, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23287475

RESUMO

One undisputed milestone of traditional oncology is neoplastic progression, which consists of a progressive selection of dedifferentiated cells driven by a chance sequence of genetic mutations. Recently it has been demonstrated that the overexpression of well-defined transcription factors reprograms somatic cells to the pluripotent stem status. The demonstration raises crucial questions as to whether and to what extent this reprogramming contributes to tumorigenesis, and whether the epigenetic changes involved in it are reversible. Here, we show for the first time that a tumor produced in vivo by a chemical carcinogen is the product of the interaction between neoplastic progression and reprogramming. The experimental model employed the prototype of ascites tumors, the Yoshida AH130 hepatoma and other neoplasias, including human melanoma. AH130 hepatoma was started in the liver by the carcinogen o-aminoazotoluene. This compound binds to and abolishes the p53 protein, producing a genomic instability that promotes both the neoplastic progression and the hepatoma reprogramming. Eventually this tumor contained 100% CD133(+) elements and pO(2)-dependent percentages of the three embryonic transcription factors Nanog, Klf4 and c-Myc. Once transferred into aerobic cultures, the minor cellular fraction expressing this triad generates various types of adherent cells, which are progressively substituted by non-tumorigenic elements committed to fibromuscular, neuronal and glial differentiation. This reprogramming appears to be accomplished stepwise, with the assembly of the triad into a sophisticated transcriptional, oxygen-dependent circuitry, in which Nanog and Klf4 antagonistically regulate c-Myc, and hence, cell hypoxia survival and cell cycle activation.


Assuntos
Desdiferenciação Celular/fisiologia , Transformação Celular Neoplásica/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Animais , Desdiferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Primers do DNA/genética , Citometria de Fluxo , Instabilidade Genômica/efeitos dos fármacos , Humanos , Fator 4 Semelhante a Kruppel , Neoplasias Hepáticas Experimentais/induzido quimicamente , Masculino , Microscopia Eletrônica , Proteína Homeobox Nanog , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Proteína Supressora de Tumor p53/metabolismo , o-Aminoazotolueno/metabolismo , o-Aminoazotolueno/toxicidade
7.
J Occup Health ; 55(1): 43-6, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23183023

RESUMO

OBJECTIVES: The purpose of this research was to develop a method for the simultaneous determination of p-Phenylazoaniline (also called 4-aminoazobenzene, AAB) and 2-methyl-4-(2-tolylazo)aniline (also called o-aminoazotoluene, AAT) in workplace air for risk assessment. METHODS: The characteristics of the proposed method, such as recovery, limit of quantitation, reproducibility and storage stability of the samples were examined. RESULTS: An air sampling cassette containing two sulfuric acid-treated glass fiber filters was chosen as the sampler. The AAB and AAT were extracted from the sampler filters by methanol and then analyzed by a high-performance liquid chromatograph equipped with a photo-diode array detector. The overall recoveries from spiked samplers were 77-98 and 85-98% for AAB and AAT, respectively. The recovery after 5 days of storage in a refrigerator exceeded 96%. The overall limits of quantitation were 5.00 and 2.50 µg/sample for AAB and AAT, respectively. The relative standard deviations, which represent the overall reproducibility defined as precision, were 0.6-1.8 and 0.5-2.2% for AAB and AAT, respectively. CONCLUSIONS: The proposed method enables 4-h personal exposure monitoring of AAB and AAT at concentrations of 21 to 2,000 µg/m3 for AAB and 10 to 2,000 µg/m3 for AAT, respectively. The proposed method is useful for estimating worker exposure to AAB and AAT.


Assuntos
Poluentes Ocupacionais do Ar/análise , Monitoramento Ambiental/métodos , Exposição Ocupacional/análise , o-Aminoazotolueno/química , p-Aminoazobenzeno/química , Cromatografia Líquida de Alta Pressão , Humanos , Saúde Ocupacional
9.
Vopr Onkol ; 57(2): 216-20, 2011.
Artigo em Russo | MEDLINE | ID: mdl-21809668

RESUMO

Pentachlorophenol, an inhibitor of metabolic activation of aminoazo dyes was administered to suckling mice prior to o-aminoazotoluene (OAT). It was followed by formation of numerous preneoplastic nodules and tumors in the lungs and liver. At the same time, 2,3,7,8-tetrachlorodibenzo-p-dioxine treatment decreased their number in the liver while slightly increasing them in the lung. A possible mechanism of aminoazo dye carcinogenicity is suggested.


Assuntos
Carcinógenos/toxicidade , Corantes/toxicidade , Fígado/patologia , Pulmão/patologia , Dibenzodioxinas Policloradas/farmacologia , Lesões Pré-Cancerosas/induzido quimicamente , o-Aminoazotolueno/toxicidade , Animais , Biotransformação/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Pentaclorofenol/farmacologia , Dibenzodioxinas Policloradas/toxicidade
10.
Toxicol Appl Pharmacol ; 255(1): 76-85, 2011 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-21672546

RESUMO

2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepatic mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car(-/-)) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car(-/-) livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor.


Assuntos
Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , o-Aminoazotolueno/toxicidade , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Proliferação de Células/efeitos dos fármacos , Receptor Constitutivo de Androstano , Família 2 do Citocromo P450 , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/fisiologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/análise , Receptores Citoplasmáticos e Nucleares/fisiologia , Esteroide Hidroxilases/genética
11.
Bull Exp Biol Med ; 152(1): 101-4, 2011 Nov.
Artigo em Inglês, Russo | MEDLINE | ID: mdl-22803052

RESUMO

Transcription factors of the FoxA family (forkhead box A) regulate cell metabolism and differentiation and maintain specificity of liver cell proteome and phenotype of mature hepatocytes. The relationship between hepatocarcinogenicity of azo compounds o-aminoazotoluene (OAT) and 3'-methyl-4-dimethylaminobenzene (3'MeDAB) for GR mice and one of the early events, modulation of the DNA-binding activity of FoxA transcription factor, was studied. Single injection of 3'MeDAB to 12-day-old mice caused liver tumors in 100% males and females similarly as OAT, a well-known mouse hepatocarcinogene. The DNA-binding activity of FoxA in the liver decreased 2.5-3 times by OAT, this resulting in a 40% reduction of glucocorticoid induction of tyrosine aminotransferase (liver-specific gene). In contrast to these, 3'MeDAB did not modify FoxA protein activities or the degree of glucocorticoid induction of tyrosine aminotransferase.


Assuntos
Compostos Azo/toxicidade , Derivados de Benzeno/toxicidade , Fatores Nucleares de Hepatócito/metabolismo , Neoplasias Hepáticas/induzido quimicamente , o-Aminoazotolueno/toxicidade , Animais , Compostos Azo/farmacologia , Derivados de Benzeno/farmacologia , Feminino , Glucocorticoides , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Ligação Proteica , Proteínas Proto-Oncogênicas c-ets/metabolismo , Ativação Transcricional/efeitos dos fármacos , o-Aminoazotolueno/farmacologia
12.
Vopr Onkol ; 56(2): 196-200, 2010.
Artigo em Russo | MEDLINE | ID: mdl-20552897

RESUMO

When used separately, diethylnitrosamine (DENA) initiates 4-6 times more neoplastic lesions in the liver of suckling mice than ortho-aminoazotoluene (OAT) lower. However, after combined treatment with either carcinogen the total number of hepatic lesions was significantly than that in mice injected with DENA only. Similar inhibition of DENA-induced hepatocarcinogenesis was observed when OAT was administered 8-12 hrs after DENA. Our findings cannot be adequately explained except by competition of the carcinogens for supposedly target molecules of protein origin, presumably, transcription factors, which contribute to generation of genetic information. They have different affinities for different compounds and, therefore, suffer different damage from the latter functioning.


Assuntos
Anticarcinógenos/farmacologia , Carcinógenos/antagonistas & inibidores , Dietilnitrosamina/antagonistas & inibidores , Neoplasias Hepáticas Experimentais/prevenção & controle , Neoplasias Pulmonares/prevenção & controle , o-Aminoazotolueno/farmacologia , Animais , Anticarcinógenos/administração & dosagem , Esquema de Medicação , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Endogâmicos ICR , Neoplasias Experimentais/prevenção & controle , Fatores de Tempo , o-Aminoazotolueno/administração & dosagem
15.
Toxicology ; 254(1-2): 91-6, 2008 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-18852010

RESUMO

The susceptibility to hepatocellular carcinoma (HCC) varies greatly within human populations in response to environmental risk agents. The mechanisms underlying differential susceptibility are still largely unknown and need to be clarified to improve HCC chemoprevention and therapeutic treatment. Inbred rodent strains with established predispositions for hepatocarcinogenesis offer the opportunity to identify intrinsic susceptibility and resistance factors. Previously, we have characterized mouse strains showing differential susceptibility to o-aminoazotoluene (OAT) and established that susceptibility does not result from OAT metabolism or genotoxicity in the livers of resistant and susceptible mice. In this study we have found that OAT differently affects hepatocyte proliferation in mice after partial hepatectomy (PH). OAT inhibited hepatocyte proliferation by 60-80% in the livers of susceptible mice, whereas resistant mice showed less than 15% inhibition. The inhibition resulted in significant delay of hepatic mass recovery in susceptible mice. OAT induced p53 stabilization and transcriptional activation in response to carcinogen treatment to the same degree in both, susceptible and resistant mice. Taken together, our data support inhibition of hepatocyte proliferation as a major cause for increased mouse susceptibility to hepatocarcinogenesis, and acceleration of functional liver recovery may offer a way to increase resistance to hepatic neoplasms. These results may have relevance to clinical observations of HCCs and implications for HCC chemoprevention and treatment.


Assuntos
Regeneração Hepática/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , o-Aminoazotolueno/farmacologia , Animais , Carcinógenos/farmacologia , Proliferação de Células/efeitos dos fármacos , Suscetibilidade a Doenças/metabolismo , Hepatectomia , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos
16.
Biochemistry (Mosc) ; 73(1): 70-5, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18294132

RESUMO

To reveal the mechanism of tumor-suppressing activity of FOXA proteins in liver, a search for potential target genes of these transcription factors involved in proliferation control was carried out. In the first step, we have used data from the literature concerning gene expression in mouse liver (high content of FOXA proteins) and kidney (FOXA expression is absent) obtained by hybridization on microchips. A search for FOXA binding sites in regulatory regions of forty differentially expressing genes involved in proliferation control was carried out using the computer method SITECON. Eleven genes containing clusters of potential FOXA sites incorporating 3-6-fold repeats of TTTG were revealed. The FOXA-specific interaction with such microsatellite sites was confirmed by gel-retardation technique using the GST-fused protein containing the DNA-binding domain of FOXA2. Six genes containing clusters of confirmed binding sites--Cul2, Cdc73, Ptk, Pdcd, Creb, and Ppp2r5d--were selected. The effect of hepatocarcinogen orthoaminoazotoluene (OAT), which lowers the FOXA activity, on expression of these genes was studied by the real-time PCR. OAT was shown to increase sharply the level of mRNA of the Cul2 and Cdc73 genes.


Assuntos
Expressão Gênica , Fatores Nucleares de Hepatócito/metabolismo , Fígado/metabolismo , Animais , Sítios de Ligação , Carcinógenos/farmacologia , Proliferação de Células , Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , RNA Mensageiro/biossíntese , Elementos Reguladores de Transcrição , o-Aminoazotolueno/farmacologia
17.
Bull Exp Biol Med ; 144(3): 338-41, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18457031

RESUMO

Selective increase of DNA-binding activity of constitutive androstane receptor was detected in rat and mouse liver in response to aminoazo dyes exhibiting hepatocarcinogenic activity for these species (ortho-aminoazotoluene for mice and 3'-methyl-4-dimethylaminobenzene for rats). Competition of azo dyes with 3H-5alpha-androst-16-ene-3alpha-ol (a well-known ligand of constitutive androstane receptor) for binding to liver cell cytosol proteins was studied. Ortho-aminoazotoluene and 3'-methyl-4-dimethylaminobenzene were better competitors for cytosol proteins from mouse and rat liver, respectively.


Assuntos
Corantes/metabolismo , Metildimetilaminoazobenzeno/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , o-Aminoazotolueno/metabolismo , Animais , Receptor Constitutivo de Androstano , Humanos , Ligantes , Neoplasias Hepáticas/induzido quimicamente , Masculino , Camundongos , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genética
18.
Bull Exp Biol Med ; 144(5): 722-4, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18683506

RESUMO

o-Aminoazotoluene was more potent than 3'-methyl-4-dimethylaminoazobenzene in modulating glucocorticoid induction of tyrosine aminotransferase and DNA-binding activity of FOXA (HNF3) in 12-day-old ICR mice. In adult animals, induction of tyrosine aminotransferase and FOXA activity were modulated by o-aminoazotoluene, while 3'-methyl-4-dimethylaminoazobenzene was ineffective. Our results suggest that FOXA proteins determine glucocorticoid induction of tyrosine aminotransferase in mice (similarly to rats).


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Glucocorticoides/farmacologia , Neoplasias Hepáticas/metabolismo , Tirosina Transaminase/metabolismo , Animais , Ativação Enzimática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Metildimetilaminoazobenzeno , Camundongos , Camundongos Endogâmicos ICR , Ligação Proteica/efeitos dos fármacos , Fatores de Tempo , o-Aminoazotolueno
19.
Bull Exp Biol Med ; 144(6): 821-4, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18856210

RESUMO

o-Aminoazotoluene in noncarcinogenic doses promoted the development of liver tumors in female ICR mice induced by administration of diethylnitrosamine during early ontogeny. Severe inflammatory infiltration and proliferation of oval cells were found in liver tissue of these animals. The concentration of free thyroxin decreased in the blood. Our results supplement published data that promoters of hepatocarcinogenesis inhibit thyroid function.


Assuntos
Carcinógenos/farmacologia , Neoplasias Hepáticas/induzido quimicamente , Fígado/patologia , Tiroxina/sangue , o-Aminoazotolueno/farmacologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina , Feminino , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos ICR
20.
Mol Carcinog ; 44(4): 223-32, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16267830

RESUMO

The effects of rat-specific hepatocarcinogen 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), mouse-specific hepatocarcinogen ortho-aminoazotoluene (OAT), non-species-specific hepatocarcinogen diethylnitrosamine (DENA), and non-carcinogenic 4'-methyl-4-dimethylaminoazobenzene (4'-MeDAB) on glucocorticoid induction of tyrosine aminotransferase (TAT) and DNA-binding activity of hepatocyte nuclear factor 3 (HNF3) family of transcription factors were investigated with carcinogen-susceptible and -resistant animals. Species-specific hepatocarcinogens 3'-MeDAB and OAT strongly inhibited glucocorticoid induction of TAT in the liver of susceptible but not resistant animals. DENA, which is highly carcinogenic for the liver of both rats and mice inhibited glucocorticoid induction of TAT in both species, while non-carcinogenic 4'-MeDAB was absolutely ineffective both in rats and mice. The inhibition of TAT activity by the carcinogens was due to reduced levels of TAT mRNA, which is most likely to be a result of the reduced rate of transcription initiation of the TAT gene. In all cases, the TAT inhibition was accompanied by significant reduction of DNA-binding activity of the HNF3 transcription factor, which is known to be critical to glucocorticoid regulation of TAT gene. We also demonstrated that the described species-specific effects of OAT and of 3'-MeDAB on HNF3 DNA-binding activity may be initiated not only by administration in vivo, but also by their direct administration to homogenate, intact nuclei or nuclear lysate, but not to nuclear extract fraction, obtained by precipitation with 0.32 g/mL of ammonium sulfate (Fraction I). We showed, that a factor responsible for this effect might be precipitated in 0.32-0.47 g/mL interval of ammonium sulfate concentration. In contrast, non-specific hepatocarcinogen DENA was effective upon being added directly to Fraction I, implying a different mechanism of its action.


Assuntos
Carcinógenos/toxicidade , Fator 3-alfa Nuclear de Hepatócito/biossíntese , Neoplasias Hepáticas Experimentais/induzido quimicamente , Fígado/efeitos dos fármacos , Metildimetilaminoazobenzeno/toxicidade , Tirosina Transaminase/biossíntese , o-Aminoazotolueno/toxicidade , Animais , Núcleo Celular/metabolismo , Dietilnitrosamina/toxicidade , Indução Enzimática , Glucocorticoides/farmacologia , Fator 3-alfa Nuclear de Hepatócito/genética , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/metabolismo , Masculino , Camundongos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Especificidade da Espécie , Tirosina Transaminase/genética , p-Dimetilaminoazobenzeno/toxicidade
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