594 results on '"Methyldimethylaminoazobenzene"'
Search Results
2. Chronic alcohol consumption prevents 8-hydroxyguanine accumulation in 3′-methyl-4-dimethylaminoazobenzene-treated mouse liver
- Author
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Yuko Ootsuyama, Takkeshi Hirano, Hiroshi Kasai, and Akinori Sakai
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Male ,medicine.medical_specialty ,Guanine ,Alcohol Drinking ,DNA Repair ,Biophysics ,Alcohol ,medicine.disease_cause ,Biochemistry ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Fragmentation (cell biology) ,Molecular Biology ,Carcinogen ,Methyldimethylaminoazobenzene ,chemistry.chemical_classification ,Reactive oxygen species ,Ethanol ,Cell Biology ,Oxidative Stress ,Cell Transformation, Neoplastic ,Endocrinology ,Liver ,chemistry ,DNA glycosylase ,Carcinogens ,Carcinogenesis ,DNA Damage - Abstract
Alcohol consumption is known to have opposing effects on carcinogenesis: promotion and prevention. In this study, we examined the effects of 12% ethanol on oxidative DNA damage accumulation and its repair in mouse livers treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), a well-known hepatic carcinogen. We previously reported that 3'-MeDAB increased 8-hydroxyguanine (8-OH-Gua) accumulation and its repair activity, accompanied by the fragmentation of 8-oxoguanine DNA glycosylase 1 (OGG1), the main repair enzyme of 8-OH-Gua. The present results showed that 12% ethanol intake attenuated the 8-OH-Gua accumulation, but not the fragmentation of OGG1 induced by 3'-MeDAB. Additionally, no significant changes in oxidative status, as monitored by lipid peroxidation (LPO), were observed among the 3'-MeDAB-treated mouse livers with/without alcohol administration. These findings suggested that 12% ethanol consumption may reduce the risk of 3'-MeDAB-induced carcinogenesis by decreasing 8-OH-Gua accumulation.
- Published
- 2009
3. Effect of Treatment of Rats with Some Chemical Carcinogens on the Stimulatory Effect of Adrenaline on Cyclic AMP Accumulation in Liver Slices
- Author
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Thoralf Christoffersen
- Subjects
Male ,medicine.medical_specialty ,Epinephrine ,Toxicology ,p-Dimethylaminoazobenzene ,chemistry.chemical_compound ,Theophylline ,Internal medicine ,Chemical carcinogens ,Cyclic AMP ,medicine ,Animals ,Nucleotide ,Carcinogen ,Methyldimethylaminoazobenzene ,Pharmacology ,chemistry.chemical_classification ,2-Acetylaminofluorene ,Stimulation, Chemical ,In vitro ,Rats ,Endocrinology ,Liver ,chemistry ,Rat liver ,Carcinogens ,medicine.drug - Abstract
The stimulatory effect of adrenaline on the formation of cyclic AMP in rat liver, measured as accumulation of the nucleotide in slices in vitro in the presence of theophylline, was found to be increased after treatment of the animals with various carcinogens for 4–8 weeks. For the compounds tested, the order of effectiveness in this respect was 2-acetylaminofluorene > 3′-methyl-4-dimethylaminoazobenzene > 4-dimethylaminoazobenzene > 2′-methyl-4-dimethyl-aminoazobenzene; the latter substance was without effect.
- Published
- 2009
4. Advanced Health Assessment in Nurse Practitioner Programs: Follow-Up Study
- Author
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John Rosselli, Frances J. Kelley, and Catharine A. Kopac
- Subjects
Attitude of Health Personnel ,education ,Nursing Methodology Research ,Nurse's Role ,Family nurse practitioner ,Diagnosis, Differential ,Nursing ,Surveys and Questionnaires ,ComputingMilieux_COMPUTERSANDEDUCATION ,Humans ,Medicine ,Nurse Practitioners ,Professional Autonomy ,Education, Nursing, Graduate ,Physical Examination ,Curriculum ,Nursing Assessment ,Qualitative Research ,General Nursing ,Methyldimethylaminoazobenzene ,Medical education ,Chi-Square Distribution ,business.industry ,Teaching ,Core competency ,Education, Nursing, Baccalaureate ,Organizational Innovation ,United States ,Oncology nursing ,Nursing Education Research ,Health assessment ,Coursework ,Clinical Competence ,business ,Inclusion (education) ,Follow-Up Studies ,Qualitative research - Abstract
The increase in advanced practice graduate programs and the inclusion of content and skills related to advanced health assessment as a core competency for practice served as the impetus for a 5-year follow-up study to track the changes, methodologies, and integration of technology into practitioner programs. The questionnaire was mailed to the faculty/schools listed as current members in the National Health Service Corps Nurse Practitioner Faculty Advocate Network. The number of responding schools was 135 (44%). The family nurse practitioner program continues to be the most offered advanced practice nursing program. Nearly all institutions offer a post-master's program and an advanced health assessment course to their clinical graduate students. Health assessment is usually taught concurrently or as a prerequisite for clinical experiences; there continues to be a strong emphasis on the physical examination component. Ethnic and cultural assessment and gerontological assessment content increased since the original study. Both class and laboratory class sizes decreased. Qualitative data that centered on differences in graduate versus undergraduate health assessment revealed a shift in focus in several areas: differential diagnoses, abnormals, and the inclusion of advanced skills. There was an emergence of more creative strategies: the use of standardized patients, online coursework, videotaping, "live" patients, and simulations.
- Published
- 2007
5. [Mutagenic activation and carcinogenicity of aminoazo dyes of ortho-aminoazotoluene and 3'-methyl-4-dimethylaminoazobenzene in experiments on suckling mice]
- Author
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V I, Kaledin, S I, Il'nitskaia, L P, Ovchinnikova, N A, Popova, L A, Bogdanova, and T S, Morozkova
- Subjects
Methyldimethylaminoazobenzene ,Salmonella typhimurium ,Mice ,Mice, Inbred ICR ,Liver Neoplasms, Experimental ,Liver ,Carcinogens ,Mice, Inbred CBA ,Animals ,Coloring Agents ,o-Aminoazotoluene ,Mutagens ,Rats - Abstract
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.
- Published
- 2015
6. Species-specific effects of the hepatocarcinogens 3′-methyl-4-dimethyl-aminoazobenzene and ortho-aminoazotoluene in mouse and rat liver
- Author
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Maria Y. Pakharukova, Konstantin Y. Kropachev, Victor F. Kobzev, V. I. Kaledin, Olga A. Timofeeva, Zoia B. Levashova, S. I. Ilnitskaya, Gennady V. Vasiliev, Tatyana I. Merkulova, and L. O. Bryzgalov
- Subjects
Hepatocyte Nuclear Factor 3-alpha ,Male ,Cancer Research ,Biology ,o-Aminoazotoluene ,Mice ,p-Dimethylaminoazobenzene ,Liver Neoplasms, Experimental ,Tyrosine aminotransferase ,Species Specificity ,In vivo ,medicine ,Animals ,Diethylnitrosamine ,RNA, Messenger ,Rats, Wistar ,Enzyme inducer ,Glucocorticoids ,Molecular Biology ,Transcription factor ,Carcinogen ,Tyrosine Transaminase ,Cell Nucleus ,Methyldimethylaminoazobenzene ,Messenger RNA ,Molecular biology ,Rats ,Hepatocyte nuclear factors ,Liver ,Biochemistry ,Enzyme Induction ,Carcinogens ,biology.protein ,Glucocorticoid ,medicine.drug - Abstract
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.
- Published
- 2005
7. Hepatic binding proteins translocating azo dye carcinogen metabolites from cytoplasm into nucleus in rats
- Author
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K Srinivasan and M.M Bhargava
- Subjects
Metabolite ,Chromosomal translocation ,Asialoglycoprotein Receptor ,Biology ,Toxicology ,DNA Adducts ,chemistry.chemical_compound ,Cytosol ,medicine ,Animals ,Carbon Radioisotopes ,Nuclear protein ,Polyacrylamide gel electrophoresis ,Cell Nucleus ,Methyldimethylaminoazobenzene ,DNA ,General Medicine ,Rats ,medicine.anatomical_structure ,chemistry ,Biochemistry ,Sephadex ,Cytoplasm ,Injections, Intravenous ,Carcinogens ,Electrophoresis, Polyacrylamide Gel ,Carrier Proteins ,Nucleus ,Food Science - Abstract
When liver cytosol prepared from rats administered [14C]-30-Methyl-N,N-dimethyl-4-aminoazobenzene was subjected to Sephadex gel chromatography, four peaks of radioactivity containing proteins (Peak-I–IV) and one peak devoid of protein (Peak-V) were obtained. Translocation of azo dye metabolites from these various cytosolic fractions into nucleus was studied in an in vitro system and a maximum of about 10% of the radioactivity associated with a particular cytosolic fraction (Peak-II) could translocate into the nuclei. Radioactivity (%) translocated did not increase upon addition of excess nuclei. Passage of this protein fraction through an immobilized protease column reduced the azo dye metabolite translocation by 65%, concomitant with the degradation of proteins. Translocation was not observed with protein-free metabolites extracted from this cytosolic fraction; addition of proteins corresponding to peak-II from normal rat liver cytosol significantly restored the metabolite translocation. This observation suggests that specific cytosolic proteins are involved in the translocation of azo dye carcinogen metabolites from liver cytoplasm into the nucleus. When the liver cytosolic proteins corresponding to this fraction (Peak-II) were iodinated with 125I-iodine and incubated with purified nuclei, translocation of three specific proteins into nucleus was observed as seen by SDS–PAGE and fluorography of nuclear proteins. Covalent binding of azo dye metabolites to DNA was not observed when cytosolic peak-II fraction containing azo dye metabolites was incubated with isolated liver DNA instead of liver nuclei. This suggests that the interaction of azo dye metabolites with nuclear macromolecules necessitate further prior processing which actually may occur in the nucleus.
- Published
- 2004
8. Resistance of DRH strain rats to chemical carcinogenesis of liver: genetic analysis of later progression stage
- Author
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Ying Yan, Ken Higashi, Yoichi Konishi, Ayumi Denda, Shunzo Onishi, Zhao-Zhu Zeng, Hiroshi Hiai, Shin Higashi, and Hikaru Ueno
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Male ,Cancer Research ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Genotype ,Quantitative trait locus ,Biology ,Ornithine Decarboxylase ,medicine.disease_cause ,Genetic analysis ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Quantitative Trait, Heritable ,Internal medicine ,medicine ,Animals ,Genetic Predisposition to Disease ,RNA, Messenger ,Crosses, Genetic ,Glutathione Transferase ,Methyldimethylaminoazobenzene ,Messenger RNA ,Chromosome Mapping ,food and beverages ,Chromosome ,Rats, Inbred Strains ,General Medicine ,Glutathione ,medicine.disease ,Molecular biology ,Rats, Inbred F344 ,Rats ,Phenotype ,Endocrinology ,chemistry ,Tumor progression ,Hepatocellular carcinoma ,Disease Progression ,Female ,Lod Score ,Carcinogenesis ,Software - Abstract
The inbred DRH rats are highly resistant to the induction of hepatocellular carcinoma (HCC) by feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Previously, we found that two quantitative trait loci (QTLs), Drhl and Drh2, significantly reduced the number, size and area of glutathione S-transferase-placental form (GST-P)-positive foci and GST-P mRNA levels in (F344 x DRH)F 2 rat livers induced by feeding 3'-Me-DAB for 8 weeks. It is unclear, however, whether these QTLs affecting pre-neoplastic lesions are also the determinants of the later stage hepatocarcinogenesis, and whether there are any additional QTLs affecting hepatocarcinogenesis in the progression stage. To answer these questions, we analyzed QTL parameters for liver tumors in 99 (F344 x DRH)F 2 rats induced by feeding 3'-Me-DAB for 20 weeks. The QTL parameters examined were GST-P mRNA, ornithine decarboxylase activity, and the number and total area of HCC/nodules macroscopically detectable on the liver surface. In composite interval mapping, we observed two major QTL peaks overlapping on the map positions of Drhl on rat chromosome 1 (RNO1) and Drh2 on RNO4, respectively. The newly mapped QTL on RNO1 affected the GST-P mRNA level at 20 weeks of 3'-Me-DAB feeding, but did not affect the number and size of tumors. The primary effect of Drhl is, therefore, to inhibit GST-P induction and to prevent enzyme altered foci (EAF) formation. On the other hand, the QTLs on RNO4, co-mapped to Drh2, affected all parameters of liver tumors examined except for the level of GST-P mRNA. The latter QTLs influenced not only the induction of GST-P and formation of EAF but also the progression of tumors in the later stage of hepatocarcinogenesis. The GST-P induction is differentially controlled by stages of hepatocarcinogenesis and the DRH resistance to carcinogenesis is principally attributed to the QTLs on RNO4 out of two resistance QTLs identified in the pre-neoplastic stage.
- Published
- 2002
9. Immunohistochemical Localization of Transforming Growth Factor Alpha in Chemically Induced Rat Hepatocellular Carcinomas with Reference to Differentiation and Proliferation
- Author
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Kazuhiro Goto, Fumiko Sano, Jiro Sugimoto, Mamoru Mutai, Miyoko Okada, Tetsuya Sakairi, Kiyoshi Kobayashi, Takayuki Tsuchiya, and Manami Kusakabe
- Subjects
Male ,TGF alpha ,Pathology ,medicine.medical_specialty ,040301 veterinary sciences ,Cellular differentiation ,Biology ,Toxicology ,030226 pharmacology & pharmacy ,Pathology and Forensic Medicine ,0403 veterinary science ,03 medical and health sciences ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,0302 clinical medicine ,medicine ,Animals ,Molecular Biology ,Cell Nucleus ,Methyldimethylaminoazobenzene ,Cell growth ,Cell Differentiation ,04 agricultural and veterinary sciences ,Cell Biology ,Transforming Growth Factor alpha ,HCCS ,Immunohistochemistry ,Rats, Inbred F344 ,digestive system diseases ,Rats ,Bromodeoxyuridine ,chemistry ,Cytoplasm ,Cell Division ,Transforming growth factor - Abstract
Hepatocellular carcinomas (HCCs) were induced in male Fischer 344 rats with dietary 3'-methyl-4-(dimethylamino)-azobenzene treatment and were classified into solid, glandular (well- or poorly differentiated), and trabecular types. Investigation of cell proliferation kinetics and immunohistochemical localization of transforming growth factor alpha (TGF-alpha) demonstrated all solid (n = 24) and poorly differentiated glandular type (n = 6) HCCs to have TGF-alpha-positive nuclei. Nuclear staining of TGF-alpha was also observed in 13 of 28 (46%) trabecular-type HCCs, whereas 12 (43%) exhibited cytoplasmic staining, and 3 (11%) were negative. As for well-differentiated glandular HCCs, 7 of 20 (35%) were positively stained in their nucleus, another 7 (35%) demonstrated antibody binding in the cytoplasm, and 6 (30%) were negative. The order for growth rate evaluated by bromodeoxyuridine (BrdU) labeling was solid (38.22%), poorly differentiated glandular (26.82%), trabecular (7.98%), and well-differentiated glandular (2.57%) types. For trabecular HCCs with nuclear, cytoplasmic, or negative TGF reactions, values were 13.39% (n = 13), 3.61% (n = 12), and 2.01% (n = 3), respectively. Likewise, BrdU-labeling indices for the counterpart groups of well-differentiated glandular type HCCs were 4.53, 1.91, and 1.29%, respectively. The results indicate that TGF-alpha expression might be linked to histopathological differentiation and cell proliferation in rat HCCs.
- Published
- 2000
10. Investigation of Possible Involvement of Several Genes Related to Development of Hepatocarcinogenesis in Rats
- Author
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Nanae Todaka, Hiroshi Hiai, Ken Higashi, Kenzo Yamashiro, Tetsuya Abe, and Ying Yan
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Molecular Sequence Data ,Biology ,medicine.disease_cause ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Insulin-Like Growth Factor II ,Transforming Growth Factor beta ,Internal medicine ,Gene expression ,medicine ,Animals ,Genetic Predisposition to Disease ,Receptor ,Carcinogen ,Glutathione Transferase ,Methyldimethylaminoazobenzene ,Messenger RNA ,Base Sequence ,Growth factor ,Insulin-like growth factor 2 receptor ,Public Health, Environmental and Occupational Health ,Rats, Inbred Strains ,General Medicine ,Glutathione ,Rats, Inbred F344 ,Rats ,Gene Expression Regulation, Neoplastic ,Enhancer Elements, Genetic ,Endocrinology ,chemistry ,alpha-Fetoproteins ,Carcinogenesis - Abstract
A comparative study on the possible involvement of several genes in the susceptibility of chemical carcinogenesis was carried out using carcinogen-resistant DRH rat and -sensitive Donryu and F344 rats. Previously, we observed that the induction of glutathione S-transferase placental form (GST-P) in the liver of Donryu rats by 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) was significantly greater than that of DRH rats. In the present study, we tentatively determined base sequences of the enhancer region including GPE-I and GPE-II (GST-P enhancers I and II) of GST-P genes of DRH, Donryu and F344 rats, but we did not observe any nucleotide polymorphism around these regions. Furthermore, the mRNA levels of silencer binding protein (NFA-1) for the GST-P promoter of rat liver were also similar in the DRH and Donryu rats. Since clonal expansion of putative preneoplastic GST-P-positive foci in the DRH rat liver was significantly suppressed during 3'-Me-DAB administration, we examined whether two opposite growth controlling factors, TGF-alpha and TGF-beta, may participate in such suppression of growth. It was supposed that mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), at least in part, activates TGF-beta preproprotein. However, we observed that the levels of M6P/IGF2R mRNA in the livers of DRH were not higher than those of Donryu rats after being fed 3'-Me-DAB for 8 weeks. Another important factor in the carcinogenesis is insulin-like growth factor II itself. Although liver tumors induced by 3'-Me-DAB in F344 had high levels of IGF-II mRNA, little IGF-II gene expression existed in normal adult livers of Donryu, F344 and DRH rats. High levels of IGF-II mRNA were detected similarly in the livers of neonates from all these three strains of rats. Finally, we detected a significant increase of AFP (alpha-fetoprotein) mRNA in the livers of Donryu rats around 6 to 8 weeks from the start of 3'-Me-DAB feeding, which is in parallel with detrimental effects of this carcinogen on these rats. A reduced induction of AFP mRNA was observed in DRH rats under the same conditions. Further study will be needed to explain the lower tumor susceptibility in the DRH rat.
- Published
- 2000
11. Reduced T Cell Response in Carcinogen-sensitive Donryu Rats Compared with Carcinogen-resistant DRH Rats
- Author
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Tsutomu Sugiura, Uki Yamashita, Ken Higashi, and Setsuko Mise-Omata
- Subjects
Antigens, Differentiation, T-Lymphocyte ,Male ,Cancer Research ,medicine.medical_specialty ,Cellular immunity ,Tertiary amine ,T-Lymphocytes ,T cell ,Lymphocyte ,Antigen-Presenting Cells ,chemical and pharmacologic phenomena ,Biology ,Article ,Natural killer cell ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,NK cell ,Hypersensitivity, Delayed ,Antigen-presenting cell ,Methyldimethylaminoazobenzene ,Rats, Inbred Strains ,Immunity, Innate ,Rats ,Killer Cells, Natural ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Delayed hypersensitivity ,Donryu rat ,Immunological competence ,Antibody Formation ,Hemocyanins ,Carcinogens ,DRH rat ,Cytokines ,Immunosuppressive Agents ,Spleen ,CD8 - Abstract
Carcinogen-resistant DRH rats were developed from carcinogen-sensitive Donryu rats, which showed a high incidence of hepatic tumors when they were exposed to 3'-methyl-4-dimethyl-amino-azobenzene (3'-MeDAB4) or other aminoazo hepatocarcinogens. In order to study the mechanism of the difference of carcinogenesis, we studied the immunological competence of Donryu rats compared with that of DRH rats. Anti-keyhole limpet hemocyanin (KLH) antibody and KLH-specific delayed hypersensitivity (DTH) responses after immunization with KLH were reduced in Donryu rats compared with DRH rats. Proliferative responses of spleen cells to KLH and nonspecific mitogens such as conconavalin A (Con A) and phytohemagglutinin (PHA) were significantly lower in Donryu rats than in DRH rats. Upon the cross-linking of T cell receptor (TCR) complex using anti-CD3 monoclonal antibody (Mab), spleen cells from Donryu rats proliferated poorly. Two other strains of rats, SD and Wistar, exhibited high responsiveness, comparable to that of DRH rats, indicating that the responsiveness of Donryu rats was impaired. The production of interleukin-2 (IL-2) upon stimulation with Con A and the responsiveness of Con A blasts to exogenous IL-2 were also attenuated in Donryu rats. In contrast to T cell responsiveness, natural killer (NK) cell activity of spleen was increased in Donryu rats. Flow cytometric analysis revealed that the expression of CD4 and CD8 on T cells was decreased in Donryu rats, though the expression of other T cell markers such as CD2, CD3 and CD5 was not different. These results indicate that Donryu rats, which have been used in many years for cancer research in Japan, have impaired immunological surveillance mechanisms. This is likely to be one of the factors accounting for the high sensitivity to chemical carcinogens and the high susceptibility to transplanted tumor cells of Donryu rats.
- Published
- 1999
12. Increased activity and expression of MAP kinase in HCC model rats induced by 3′-methyl-4-dimethylamino-azobenzene
- Author
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Naotake Hashimoto, Kenji Tokita, Azuma Kanatsuka, Mitsutaka Toyoda, Yasushi Saito, Barry J. Goldstein, Osamu Yokosuka, and Yasuo Suzuki
- Subjects
Male ,MAPK/ERK pathway ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Blotting, Western ,MAPK cascade ,medicine.disease_cause ,Rats, Sprague-Dawley ,Reference Values ,Internal medicine ,medicine ,Animals ,Phosphorylation ,Protein kinase A ,Methyldimethylaminoazobenzene ,Hepatology ,biology ,Liver Neoplasms ,Blotting, Northern ,Phosphoproteins ,medicine.disease ,Rats ,Insulin receptor ,Endocrinology ,Liver ,Mitogen-activated protein kinase ,Insulin Receptor Substrate Proteins ,biology.protein ,Tyrosine ,Mitogen-Activated Protein Kinases ,Signal transduction ,Liver cancer ,Carcinogenesis - Abstract
The ras-mitogen-activated protein kinase (MAPK) cascade plays an important role not only in the mitogenic signal transduction pathway but also in the development of cancer, and it is believed to be one of the important regulators in normal hepatocytes and hepatocellular carcinoma. The aim of this study was to determine the role of insulin receptor substrate-1 and the MAPK cascade in rats with hepatocellular carcinoma induced by 3'-methyl-4-dimethylamino-azobenzene (3'-MeDAB).Liver cancer was induced in rats by feeding 3'-MeDAB, and the changes in expression of IRS-1 and MAPK were analyzed in tumorous, non-tumorous and control liver.Expression of insulin receptor substrate-1 (IRS-1) showed a 1.4-fold increase at protein level in the tumors (p0.01), but the tyrosine phosphorylation of IRS-1 did not differ between the tumor and control liver. Expression of MAPK and its activity were elevated 4.5-7.5-fold (p0.01) and 4.6-fold (p0.01) in the tumor compared with control liver. In non-tumorous lesions from rats fed with 3'-MeDAB, expression of MAPK, but not IRS-1, increased significantly (p0.01). Between tumorous and adjacent non-tumorous lesions, there was a significant difference in MAPK expression (p0.05) and activities (p0.05).The increased expression of MAPK may play an important role in the progression or initiation of HCC in this rat model.
- Published
- 1999
13. Genetic properties for the suppression of development of putative preneoplastic glutathione S-transferase placental form-positive foci in the liver of carcinogen-resistant DRH strain rats
- Author
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Ken Higashi, Sadao Gotoh, Ying Yan, Yoichi Konishi, Taneaki Higashi, Tetsuya Abe, Yukiyo Fukamachi, Kunio Ikemura, Ayumi Denda, Wakashi Kitayama, and Masayoshi Miura
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Biology ,medicine.disease_cause ,Isozyme ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Inbred strain ,Internal medicine ,medicine ,Animals ,Hepatectomy ,Diethylnitrosamine ,RNA, Messenger ,Telomerase ,Crosses, Genetic ,Carcinogen ,Glutathione Transferase ,Methyldimethylaminoazobenzene ,Nitrates ,DNA synthesis ,Body Weight ,Rats, Inbred Strains ,DNA ,Organ Size ,Glutathione ,Blotting, Northern ,Rats, Inbred F344 ,Rats ,Endocrinology ,Glutathione S-transferase ,Lead ,Oncology ,chemistry ,biology.protein ,Carcinogenesis ,Precancerous Conditions ,Cell Division - Abstract
The post-initiation stage of hepatocarcinogenesis was investigated in carcinogen-resistant inbred DRH rats and the parental strain, carcinogen-sensitive Donryu rats. Male rats at 5 weeks of age from both strains were treated with N-nitrosodiethylamine (200 mg/kg i.p.) followed by feeding with a diet containing 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) from 2 weeks later and were then subjected to partial hepatectomy at 1 week later. At 8 weeks after the start of treatment, the mean area occupied by glutathione S-transferase placental form (GST-P)-positive lesions was about 30% in Donryu rats but less than 4% in DRH rats despite the presence of comparable numbers of foci in the livers of both strains. These observations suggested that clonal expansion of GST-P-positive foci in DRH rat liver was significantly suppressed under these conditions. Furthermore, this genetic property was dominantly inherited in the F1 rats by crosses of DRH and carcinogen-sensitive inbred F344 rats; that is, the induction of GST-P mRNA in the livers of F344 x DRH F1 rats was dominantly suppressed after administration of 3'-Me-DAB for 8 weeks as compared with parental F344 rats under the same conditions. We compared the intrinsic properties related to growth potential of liver cells between adult DRH and Donryu rats. DRH rat liver showed retarded and/or reduced DNA synthesis after partial hepatectomy or a single i.v. injection of lead nitrate and lower activity of telomerase induced by 3'-Me-DAB administration for 1 week, as compared with the Donryu rat liver. The intrinsic properties observed in this study may be related, at least in part, to the low incidence of liver tumors induced by hepatocarcinogens in DRH rats.
- Published
- 1999
14. Studies on the Multidrug Resistance Gene Expression in the Livers of Rats Associated with Different Susceptibility of Hepatocarcinogenesis
- Author
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Ken Higashi, Tetsuya Abe, Ying Yan, Sadao Gotoh, Nanae Todaka, and Yukiyo Fukamachi
- Subjects
Male ,medicine.medical_specialty ,Anion Transport Proteins ,Gene Expression ,Cholestasis ,Internal medicine ,Gene expression ,medicine ,Animals ,Cytotoxic T cell ,Genetic Predisposition to Disease ,RNA, Messenger ,Methyldimethylaminoazobenzene ,Messenger RNA ,Chemistry ,Liver Neoplasms ,Public Health, Environmental and Occupational Health ,Rats, Inbred Strains ,Rat strain ,General Medicine ,medicine.disease ,Drug Resistance, Multiple ,Multidrug Resistance Gene ,Rats ,Endocrinology ,Liver ,Mrna level ,Rat liver ,Genes, MDR ,Tumor Suppressor Protein p53 ,Carrier Proteins - Abstract
Inbred carcinogen-resistant DRH rat strain developed from the closed colony Donryu rats on the basis of selective markers such as poor induction of gamma-glutamyltranspeptidase and marked reduced incidences of liver tumors during 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) administration, which took more than 10 years. Previously, we observed that the Donryu rat liver was quite sensitive to both DNA-damaging and cytotoxic effects of 3'-Me-DAB, while the DRH rat liver showed tolerance to 3'-Me-DAB under the same conditions. In the present study, we examined mRNA levels related to the cytotoxic drug resistance mechanism in the livers of DRH and Donryu rats using RT-PCR. Contrary to our expectation, we observed rather similar levels of mRNAs between the two rat strains under the following conditions: i) mdr1 mRNA induction after 3'-Me-DAB administration. ii) MLP-2 mRNA reduction by 3'-Me-DAB administration, iii) MLP-2 mRNA induction after cholestasis and iv) constitutive levels of cMOAT gene expression. On the other hand, the levels of p53 mRNA and p53 protein in the Donryu rat liver were higher than those in DRH rat liver during 3'-Me-DAB administration, suggesting that the former were more sensitive to 3'-Me-DAB than DRH rat under these conditions. In conclusion, we failed to demonstrate the difference in the cytotoxic drug resistance mechanism between DRH and Donryu rats at least under the conditions examined in this study.
- Published
- 1999
15. Different Responses Other than the Formation of DNA-adducts between the Livers of Carcinogen-resistant Rats (DRH) and Carcinogen-sensitive Rats (Donryu) to 3′-Methyl-4-dimethylaminoazobenzene Administration
- Author
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Kaori Yamamura, Masayoshi Ichiba, Yukiyo Fukamachi, Takeshi Hirano, Ken Higashi, Tetsuya Abe, Ying Yan, Sadao Gotoh, Tsutomu Sugiura, and Taneaki Higashi
- Subjects
Male ,Cancer Research ,Programmed cell death ,Methyltransferase ,DNA repair ,Drug Resistance ,Gene Expression ,Biology ,Carcinogen resistance ,Sensitivity and Specificity ,Article ,DNA Adducts ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,DNA adduct ,Animals ,RNA, Messenger ,Carcinogen ,Methyldimethylaminoazobenzene ,Rats, Inbred Strains ,Glutathione ,key words ,Molecular biology ,Rats ,Heme oxygenase ,Nongenotoxic effect ,Glutathione S-transferase ,Gene Expression Regulation ,Liver ,Oncology ,chemistry ,Biochemistry ,3′‐Me‐DAB ,Carcinogens ,biology.protein ,Phosphorus Radioisotopes ,Precancerous Conditions ,DNA Damage ,Glutathione S‐transferase - Abstract
Carcinogen-resistant inbred DRH rats developed from the Donryu strain showed a remarkably low incidence of liver tumors when they were fed diets containing hepatocarcinogens such as 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). In this work, we examined various characteristics of male DRH and Donryu rats during 3'-Me-DAB administration for 8 weeks. 32 P-Postlabeling analysis showed that essentially similar levels of DNA-adducts were generated by the metabolites of 3'-Me-DAB in the livers of these two strains of rats at several time points. However, both GADD45 (growth arrest and DNA damage-inducible) and O 6 -methylguanine methyltransferase (putatively DNA damage-inducible) mRNA levels were increased significantly in Donryu rat livers, but were increased to a lesser extent in DRH rats. [ 3 H]Thymidine incorporation into hepatic DNA began to increase around 10 to 20 days after the start of 3'-Me-DAB administration in Donryu rats probably due to DNA repair, while no significant change occurred in DRH rats under the same conditions. Furthermore, inductions of heme oxygenase (due to degradation of heme-proteins) and hepatocyte growth factor (HGF; cell death and regeneration of hepatocytes) mRNAs were greater in Donryu rat livers than those of DRH, suggesting that the former were more sensitive to cytotoxic effects of 3'-Me-DAB than the latter. Another remarkable difference observed between these two strains was the significant induction of cytochrome P-450 2E1 mRNA in Donryu rat livers; this may contribute to the generation of reactive oxygen intermediates. Finally, increases of glutathione S-transferase (P-form) and γ-glutamyltranspeptidase mRNAs as marker enzymes of preneoplastic changes of hepatocytes were clearly seen only in Donryu rat livers at 6 to 8 weeks after the start of 3'-Me-DAB administration. These results indicate that the different susceptibility to hepatocarcinogenesis between these two strains of rats may arise from events other than the DNA adduct formation.
- Published
- 1998
16. Studies on the Microsomal Cytochrome P450s in the Livers of Carcinogen-resistant and Sensitive Rats during Long-Term Administration of 3'-Methyl-4-Dimethylaminoazobenzene
- Author
-
Yukiyo Fukamachi, Toshihiro Kawamoto, Ying Yan, Ken Higashi, Mihi Yang, Takeshi Hirano, and Kaori Yamamura
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Cytochrome ,3 methyl 4 dimethylaminoazobenzene ,Liver Neoplasms, Experimental ,Cytochrome P-450 Enzyme System ,Cytochrome P-450 CYP1A2 ,Cytochrome P-450 CYP2E1 ,Internal medicine ,Cytochrome P-450 CYP1A1 ,medicine ,Animals ,Carcinogen ,Methyldimethylaminoazobenzene ,biology ,Chemistry ,Public Health, Environmental and Occupational Health ,CYP1A2 ,Cytochrome P450 ,Rats, Inbred Strains ,General Medicine ,CYP2E1 ,Rats ,Endocrinology ,Microsomes, Liver ,biology.protein ,Microsome ,Disease Susceptibility - Abstract
Time-course studies on the microsomal cytochrome P450s in the livers of carcinogen-resistant (DRH) and sensitive (Donryu) rats were carried out during a long-term administration of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Total contents of the microsomal cytochrome P450s were gradually reduced with time in the Donryu rat livers, while those in the DRH rats did not alter significantly under these conditions. The activities of several isoforms of cytochrome P450 (CYP1A1, CYP1A2, and CYP2E1) were determined separately during these experimental periods. However, we could not obtain satisfactory evidence which may explain the different susceptibility to chemical carcinogenic actions in the livers between DRH and Donryu rats. Lower total contents of cytochrome P450s in the Donryu rats during the later stage may be due to the hepatic injuries caused by long-term administration of 3'-Me-DAB.
- Published
- 1997
17. Correlation between serum prolactin levels and hepatocellular tumorigenesis induced by 3'-methyl-4-dimethylaminoazobenzene in mice
- Author
-
R Yamamoto, Masaharu Tatsuta, Hiroyasu Iishi, Kanda Y, Takashi Yamamoto, Koji Koike, M Tsuji, A Miyake, and N. Terada
- Subjects
Adenoma ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,Biology ,Dopamine agonist ,Mice ,Liver Neoplasms, Experimental ,Renal capsule ,Internal medicine ,medicine ,Animals ,Bromocriptine ,Methyldimethylaminoazobenzene ,Dopamine antagonist ,Estrogens ,Nodule (medicine) ,Prolactin ,Mice, Inbred C57BL ,Transplantation ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Estrogen ,Pituitary Gland ,Perphenazine ,Female ,medicine.symptom ,Research Article ,medicine.drug - Abstract
Ovariectomy at 1 month of age promotes development of hepatocellular adenomatous nodules in female C57BL/6 x DS-F1 mice treated neonatally with 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Implantation of oestradiol-17 beta (E2) pellets at 1 month of age suppresses nodule development. Since E2 increases serum levels of prolactin, high serum levels of prolactin in mice that have received implants of E2 pellets may play a role in the suppression of hepatocellular tumorigenesis. Therefore, to investigate the role of prolactin in hepatocellular tumorigenesis, we examined development of adenomatous nodules in female mice that had been treated neonatally with 3'-Me-DAB and had undergone ovariectomy at 1 month of age, under various serum levels of prolactin. Treatment of these mice with perphenazine (dopamine antagonist) from 6 months of age or transplantation of pituitary glands under the renal capsule at 6 months of age markedly increased serum levels of prolactin and significantly suppressed the incidence of adenomatous nodules at 12 months of age. Implantation of E2 pellets at 1 month of age increased serum levels of prolactin to a greater extent and further decreased the incidence of adenomatous nodules. Treatment of mice that had received implants of E2 pellets at 1 month of age with bromocriptine (dopamine agonist) from 6 months of age decreased serum levels of prolactin, and was accompanied by an increase in the incidence of nodules. The present results showed that an increase in serum levels of prolactin was accompanied by a decrease in incidence of liver tumours induced by 3'-Me-DAB in mice, suggesting a suppressive effect of prolactin on liver tumorigenesis in mice. Thus, it is possible that the suppressive effect of oestrogen on liver tumorigenesis in mice is mediated, at least in part, by prolactin.
- Published
- 1995
18. Mutagenicity of 3'-methyl-N,N-dimethyl-4-amino azobenzene metabolites and related compounds
- Author
-
Yukio Mori, Kazumi Toyoshi, Toshiro Niwa, and Toshiro Hori
- Subjects
Salmonella typhimurium ,endocrine system ,Cancer Research ,Salmonella ,Cellular respiration ,Stereochemistry ,Mutagen ,medicine.disease_cause ,chemistry.chemical_compound ,Structure-Activity Relationship ,medicine ,Hydroxymethyl ,Methyldimethylaminoazobenzene ,biology ,Molecular Structure ,Mutagenicity Tests ,Aryl ,fungi ,food and beverages ,General Medicine ,biology.organism_classification ,Biochemistry ,chemistry ,Azobenzene ,Bacteria ,Methyl group ,Mutagens - Abstract
To elucidate the mechanism of metabolic activation of 3'-methyl-N,N-dimethyl-4-aminoazobenzene (3'-Me-DAB), the mutagenicity of its metabolites and some related azo compounds towards Salmonella typhimurium TA-98 and TA-100 was investigated. Mutagenicity of the metabolites, either N-demethylated or oxidized at the 3'-methyl group, was expressed only in the presence of a 9000 g supernatant of rat liver homogenate (S-9 mix). Of these metabolites, 3'-hydroxymethyl-aminoazo compounds showed potent mutagenic activity towards S. typhimurium TA-98 and TA-100 and gave clear-cut linear dose-response curves. In contrast, 3,3'-bis-(chloromethyl)azobenzene, a model compound for the reactive ester of a 3'-hydroxymethyl-azo compound having no 4-amino group, exerted mutagenicity on both strains of bacteria in the absence of S-9 mix and was, therefore, a direct mutagen. On the other hand, with the exception of 3'-Me-4'-OH-DAB and p-phenylenediamine and its N-methyl and N,N-dimethyl derivatives, all the aryl hydroxylated or azo-reduced metabolites were not mutagenic towards the bacteria. These findings indicate that the 3'-hydroxymethyl group is important in the expression of mutagenicity by these azo compounds and that oxidative metabolism of the 3'-methyl group in 3'-Me-DAB may be one of the mutagenic activation reactions.
- Published
- 2012
19. Elevation of hepatic levels of metallothionein during experimental carcinogenesis
- Author
-
Haruna Tamano, Atsushi Takeda, Shoji Okada, and Akihiko Hoshino
- Subjects
Male ,medicine.medical_specialty ,Lung Neoplasms ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,medicine.disease_cause ,Biochemistry ,Inorganic Chemistry ,Mice ,Cricetinae ,Internal medicine ,medicine ,Animals ,Metallothionein ,Rats, Wistar ,Methyldimethylaminoazobenzene ,chemistry.chemical_classification ,Lung ,Mesocricetus ,Biochemistry (medical) ,Neoplasms, Experimental ,General Medicine ,medicine.disease ,Rats ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Endocrinology ,Enzyme ,Liver ,Pancreatitis ,chemistry ,Hepatocellular carcinoma ,Adenocarcinoma ,Carcinogenesis - Abstract
From the early stage of pancreatic adenocarcinoma in hamsters and also of hepatocellular carcinoma in rats, induced by treatment with N-nitrosobis (2-oxopropyl)amine and 3'-methyl-dimethylaminoazobenzene, respectively, hepatic levels of metallothionein (MT) were found to be continuously elevated. In the hepatoma-induced rats, this elevation preceded that of serum gamma-glutamyl transpeptidase activity, a marker enzyme for hepatocellular carcinoma. These results indicate that, in the course of chemical carcinogenesis, the elevation of hepatic MT level occurred and continued from the early stage of carcinogenesis. This type of elevation of hepatic MT level was also observed in lung metastasis-induced mice. On the other hand, in rats with pancreatitis caused by the administration of deoxycholate, the hepatic level of MT rose only transiently.
- Published
- 1994
20. Gomisin A, a lignan component of Schizandora fruits, inhibits development of preneoplastic lesions in rat liver by 3′-methyl-4-dimethylamino-azobenzene
- Author
-
Y. Ohtaki, Masaaki Nomura, M. Aburada, Kenichi Miyamoto, K. Sudo, Tatsuo Aizawa, T. Hida, and M. Nakachiyama
- Subjects
Male ,Cancer Research ,Population ,Dioxoles ,Biology ,Pharmacology ,medicine.disease_cause ,Lignans ,Cyclooctanes ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,medicine ,Animals ,Anticarcinogenic Agents ,education ,Anticarcinogen ,Glutathione Transferase ,Cell Nucleus ,Methyldimethylaminoazobenzene ,Lignan ,education.field_of_study ,Ploidies ,Body Weight ,Organ Size ,Glutathione ,Rats ,Isoenzymes ,Liver ,Oncology ,chemistry ,Biochemistry ,Phenobarbital ,Gomisin A ,Tumor promotion ,Carcinogenesis ,Precancerous Conditions ,Drugs, Chinese Herbal ,medicine.drug - Abstract
The effects of gomisin A, a lignan component of Schizandra fruits, on development of preneoplastic lesions in the liver after a short-term (3 weeks) feeding of 3′-methyl-4-dimethyl-aminoazobenzene (3′-MeDAB) to male Donryu rats were investigated, and compared with the effects of phenobarbital. Gomisin A inhibited both increases of the level of glutathione-S-transferase placental form (GST-P) and the number and size of GST-P positive foci in the liver increased after treatment with 3′-MeDAB. Moreover, although the population of diploid nuclei was increased and that of tetraploid nuclei was decreased by pretreatment with 3′-MeDAB, gomisin A returned this to near the normal ploidy pattern. But phenobarbital increased the level of GST-P and the number and size of GST-P positive foci with little affect on the ploidy population changed by 3′-MeDAB. Thus, the effect of gomisin A on hepatocarcinogenesis was inhibitory in contrast with that of phenobarbital. This study suggests that gomisin A is a candidate for a chemopreventive drug inhibiting the promotion process in hepatocarcinogenesis.
- Published
- 1994
21. Immunocytochemical Investigation of Rat .GAMMA.-Glutamyl Transpeptidase in Chemically-Induced Hepatocarcinogenesis Using Monoclonal Antibody
- Author
-
Kei Kashima, Yoshihiro Kitagawa, Motomu Kashiwadani, Yasuhiko Ibata, Masaki Iwai, and Kenjiro Yasuda
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Histology ,medicine.drug_class ,Bile Duct Epithelium ,Cell ,Monoclonal antibody ,Bone canaliculus ,digestive system ,Epithelium ,Immunoenzyme Techniques ,Liver Neoplasms, Experimental ,medicine ,Animals ,Microscopy, Immunoelectron ,Methyldimethylaminoazobenzene ,biology ,Chemistry ,Bile Canaliculi ,Cell Membrane ,Antibodies, Monoclonal ,gamma-Glutamyltransferase ,Rats ,Staining ,Membrane ,medicine.anatomical_structure ,Monoclonal ,biology.protein ,Antibody - Abstract
An immunocytochemical study using a monoclonal antibody showed the presence of gamma-glutamyl transpeptidase (gamma-GTP) in the bile duct epithelium of the normal adult rat liver, while a slight immunoreactivity for gamma-GTP could be observed on the membranes of bile canaliculi (the membranes of hepatocytes facing the lumen of bile canaliculi). In hepatocarcinogenesis induced by 3'-methyl-4-dimethylaminoazobenzene, no immunoreactivity was detected in alpha-fetoprotein-positive cholangiolar "oval" cells, though it was detected on the membranes of bile canaliculi. In livers with hyperplastic nodules, gamma-GTP immunoreactivity was observed in clusters, with two different staining patterns. In one pattern, gamma-GTP was present not only on the membranes of bile canaliculi, but also on the membranes facing the Disse's space or the lateral cell surface of hepatocytes. In the other pattern, gamma-GTP immunoreactivity was seen on the membranes of the dilated bile canaliculi. In livers with developing hepatocellular carcinomas, the immunoreactivity was present on the membranes of irregularly dilated bile canaliculi in malignant cells.
- Published
- 1994
22. Effect of Voluntary Exercise on 3'-Methyl-4-Dimethylaminoazobenzene-lnduced Hepatomas in Male Jc1: Wistar Rats
- Author
-
Yukiko Minegishi, Tsuyoshi Watanabe, Hiroshi Osanai, and Tadashi Ikuyama
- Subjects
Male ,medicine.medical_specialty ,Food intake ,Physical Exertion ,Physical exercise ,Biology ,Liver weight ,General Biochemistry, Genetics and Molecular Biology ,3 methyl 4 dimethylaminoazobenzene ,Eating ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Gamma-glutamyltransferase ,Methyldimethylaminoazobenzene ,gamma-Glutamyltransferase ,Alkaline Phosphatase ,Rats ,Endocrinology ,Liver ,Turnover ,biology.protein ,Alkaline phosphatase ,medicine.symptom ,Weight gain - Abstract
The effect of voluntary exercise on 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB)-induced hepatomas was investigated in male Jc1:Wistar rats. Beginning at 10 weeks of age, animals were divided into two groups (sedentary and exercise) and housed in individual cages. Food intake and wheel exercise were automatically controlled in the cages of the exercise group. Body weights were monitored throughout the study. Food availability was controlled in order to equate length and weight gain. From 27 weeks to termination of the study at 62 weeks, all animals were administered 3'-Me-DAB in the diet at a dose level of 0.0177 g/day/kg body wt. All animals were sacrificed at 62 weeks of age. The incidence of hepatomas was significantly lower in the exercise group as compared with the sedentary group (0% and 65%, respectively). Liver weight was significantly greater in the exercise group compared with sedentary animals without hepatomas. The weight of epididymal fat pads was significantly lower in the exercise group. Serum alkaline phosphate was significantly higher in the exercise group as compared with the sedentary group. Serum gamma-glutamyl-transpeptidase levels were higher in the sedentary group than in the exercise group. In addition, gamma-glutamyl-transpeptidase levels were significantly higher in sedentary animals with hepatomas than in sedentary animals without hepatomas. These results demonstrate that voluntary exercise decreases 3'-Me-DAB-induced hepatomas and that this decrease is associated with an increase in serum alkaline phosphatase and a decrease in serum gamma-glutamyl-transpeptidase levels.
- Published
- 1993
23. Aspirin Shares a Short-Term Effect, Inhibition of Pyruvate Kinase Activity with Tumor-Promoting Agents, but Fails to Promote Rat Liver Carcinogenesis
- Author
-
Susumu Ynanagi, Yoshio Hiasa, and Mariko Yamashita
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Period (gene) ,Pyruvate Kinase ,Biology ,medicine.disease_cause ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Term effect ,Rats, Wistar ,Methyldimethylaminoazobenzene ,Aspirin ,Cocarcinogenesis ,Body Weight ,Promoter ,Organ Size ,General Medicine ,Rats ,Cholesterol ,Endocrinology ,Oncology ,Pyruvate kinase activity ,Rat liver ,Carcinogenesis ,Pyruvate kinase ,medicine.drug - Abstract
Since apsirin was found to cause a persistent decrease in pyruvate kinase activity, which is a prominent characteristic of the hepatic promoters, the effect of aspirin on hepatic tumorigenesis in the rat has been studied. Male Wistar rats were initiated with a diet containing 0.06% 3′-methyl-4-dimethylamino-azobenzene for 4 weeks. They were divided into 3 groups and each group was fed one of the following diets containing either 0, 0.5 or 1 % aspirin. At the end of a 58-week experimental period, no differences were observed in the incidence of hepatic lesions and hepatocellular carcinomas among the groups. Thus, it was concluded that aspirin does not promote nor inhibit the postinitiation step of hepatic tumorigenesis in the rat.
- Published
- 1993
24. Suppressive effect of estrogen on hepatocellular tumorigenesis induced in mice by 3′-methyl-4-dimethylaminoazobenzene
- Author
-
H. Iishi, M. Tatsuta, Reiko Yamamoto, Nobuyuki Terada, and Motomu Tsuji
- Subjects
medicine.medical_specialty ,Ratón ,medicine.drug_class ,Ovariectomy ,Biology ,Toxicology ,medicine.disease_cause ,Ovarian hormone ,Adenoma, Liver Cell ,Pathology and Forensic Medicine ,3 methyl 4 dimethylaminoazobenzene ,Mice ,Internal medicine ,medicine ,Animals ,Drug Implants ,Methyldimethylaminoazobenzene ,Estradiol ,Liver Carcinogenesis ,Incidence (epidemiology) ,Liver Neoplasms ,Ovary ,Cell Biology ,General Medicine ,Mice, Inbred C57BL ,Endocrinology ,Estrogen ,Ovariectomized rat ,Female ,Carcinogenesis - Abstract
Summary Treatment of female C57BL/6 × DS-F 1 mice with 3′-methyl-4-dimethylaminoazobenzene (3′-Me-DAB) neonatally resulted in the development of hepatocellular adenomatous nodules. Ovariectomy at 1 month of age greatly hastened the time of appearance of these nodules and significantly increased their incidence. The incidence of adenomatous nodules in females ovariectomized at 1 month of age was about 70 % at 12 months of age, and was decreased to 4 % by implantation of a pellet containing estradiol- 17 s (E 2 pellet) at 1 month of age (at the time of ovariectomy). The incidence of adenomatous nodules at 12 months of age was not decreased significantly when the implanted E 2 pellet was removed at 4 or 6 months of age, but was decreased significantly when it was removed at 8 or 10 months of age. Implantation of E 2 pellets into ovariectomized females at 4 and 6 months of age decreased the incidence of adenomatous nodules as effectively as their implantation at 1 month of age. The implantation of E 2 pellets into ovariectomized females at 8 or 10 months of age resulted in significantly lower incidences of adenomatous nodules at 12 months of age, than that in females ovariectomized at 1 month of age. The present results suggest that the ovarian hormone, estrogen suppresses the development of hepatocellular tumors induced by 3′-Me-DAB, exerting its effect from about 6 months of age.
- Published
- 1993
25. Anticarcinogenic effects of some Indian plant products
- Author
-
V.M. Sivaramakrishnan and K. Aruna
- Subjects
Male ,Cuminum ,Adenocarcinoma ,Toxicology ,Eating ,Mice ,Liver Neoplasms, Experimental ,Stomach Neoplasms ,Poppy ,Botany ,Benzo(a)pyrene ,Papaveraceae ,Animals ,Anticarcinogenic Agents ,Rats, Wistar ,Spices ,Legume ,Methyldimethylaminoazobenzene ,biology ,Traditional medicine ,Body Weight ,food and beverages ,General Medicine ,Ocimum ,biology.organism_classification ,Rats ,Disease Models, Animal ,Papaver ,Seeds ,Carcinoma, Squamous Cell ,Plants, Edible ,Solanum ,Food Science - Abstract
The anticarcinogenic properties of some commonly consumed spices and leafy vegetables were investigated. The effects of feeding the plant products on the induction of squamous cell carcinomas in the stomachs of Swiss mice by feeding benzo[a]pyrene(B[a]P) and on the induction of hepatomas in Wistar rats by feeding 3'-methyl-4-dimethylaminoazobenzene (3'MeDAB) were investigated. Among the nine plant products tested, cumin seeds (Cuminum cyminum Linn) and basil leaves (Ocimum sanctum Linn) significantly decreased the incidence of both B[a]P-induced neoplasia and 3'MeDAB-induced hepatomas. Poppy seeds (Papaver somniferum Linn) significantly inhibited B[a]P-induced neoplasia alone, while the other plant products, asafoetida, kandathipili, turmeric, drumstick leaves, solanum leaves and alternanthera leaves were ineffective. These results suggest that cumin seeds, basil leaves and to a lesser extent poppy seeds, which are all widely used in Indian cooking, may prove to be valuable anticarcinogenic agents.
- Published
- 1992
26. Changes in .ALPHA.2- and .BETA.-Adrenoceptors in Hepatocytes from Rats during Treatment with 3'-Methyl-4-dimethylaminoazobenzene
- Author
-
Masaaki Nomura, Keiko Kohei, Fujiko Sanae, and Ken-ichi Miyamoto
- Subjects
medicine.medical_specialty ,Tertiary amine ,Adenylate kinase ,Propranolol ,In Vitro Techniques ,Cyclase ,Clonidine ,Internal medicine ,Receptors, Adrenergic, beta ,medicine ,Prazosin ,Animals ,Iodocyanopindolol ,Methyldimethylaminoazobenzene ,Pharmacology ,Chemistry ,Rats, Inbred Strains ,Receptors, Adrenergic, alpha ,Rats ,Yohimbine ,Endocrinology ,Liver ,Pindolol ,Catecholamine ,Female ,Cyclase activity ,Adenylyl Cyclases ,medicine.drug - Abstract
A 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) containing diet was given to 6 weeks old female Donryu rats, and the number of adrenoceptors and the response of adenylate cyclase in the hepatocytes were measured. The treatment with 3'-MeDAB Ied to rapid increases in [125I]-iodocyanopindolol ([125I] ICYP)- and [3H] clonidine-binding sites to hepatic membranes without significant changes in the Kd values. The number or β-adrenoceptors defined by [125I] ICYP binding sites was increased with a biphagic mode. The [3H] clonidine binding reached a peak 2 weeks after the start of the carcinogen diet and then began a slow descent. The α2-adrenoceptor was defined by [3H] clonidine binding being selectively inhibited by an α2-antagonist, yohimbine, but not by an α1-antagonist, prazosin, or a β-antagonist propranolol. Catecholamine responsiveness to adenylate cyclase in hepatocytes also increased during treatment with 3'-MeDAB. However, the efficacy of norepinephrine (NE) in activating cyclase was lower than that of isoproterenol (IPN) during 4 to 8 weeks of the carcinogen diet. The difference between the efficacies of IPN and NE resulted from inhibiting adenylate cyclase through α2-adrenoceptors by NE. Therefore, we noticed that the increasing pattern of the number of β-adrenoceptors did not always parallel IPN-stimulated adenylate cyclase activity and that the increase in the number of α2-adrenoceptors preceded the difference between the efficacies of IPN and NE in activating adenylate cyclase. These findings suggest that the emergence of β- and α2-adrenoceptors occurs before the receptors are able to be coupled with the guanine-nucleotide binding proteins in the adenylate cyclase system in the early stage of hepatocar cinogenesis induced by 3'-MeDAB.
- Published
- 1992
27. Different Effects of Carbon Tetrachloride on Carcinogen-induced Hepatocellular Carcinoma and Normal Liver of the Rat: Lowered Lipid Feroxidation and Accelerated Necrosis in Cancer
- Author
-
Yutaka Tsutsumi, Keiichi Watanabe, Susumu Takekoshi, Masayuki Shinoda, Nirush Lertprasertsuke, Yorihiro Yamamoto, and Etsuo Niki
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Necrosis ,Hepatocellular carcinoma ,Thiobarbituric acid ,Lipid peroxidation ,Ascorbic Acid ,Article ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Vitamin C ,Carbon Tetrachloride ,Methyldimethylaminoazobenzene ,chemistry.chemical_classification ,Fatty Acids ,Fatty liver ,Fatty acid ,Thiobarbiturates ,Ascorbic acid ,medicine.disease ,Rats ,Fatty Liver ,Polyunsaturated fatty acid ,Endocrinology ,Liver ,Oncology ,chemistry ,Carbon tetrachloride ,medicine.symptom ,Azo Compounds - Abstract
To investigate molecular responses to lipid peroxidative stimuli in neoplastic cells, lipid peroxidation was induced in liver of rats bearing 3′‐methyl‐4‐dimethylaminoazobenzene‐induced hepatocellular carcinoma by injecting a high dose of carbon tetrachloride (CCL4), a strong lipoperoxidative reagent. Normal rat livers with or without CCl4 treatment served as controls. CCL4, administration markedly provoked fatty metamorphosis, visualized by oil red O staining, in normal livers while minimal fatty changes were seen in hepatocellular carcinomas, where necrosis was often observed instead. After CCl4 treatment, the thiobarbituric acid values (representing levels of lipid peroxides in the tissue) were increased two–fold in the untreated normal liver, but were unchanged in the cancer tissue. Levels of vitamin C, an acutely reactive antioxidant, measured by high‐performance liquid chromatography were not influenced by the CCL4 injection in the cancer tissue whereas a significant decrease was evident in normal livers. The total fatty acid content, measured by gas chromatography, was significantly lower in the cancer tissue than in the normal liver while the ratio of polyunsaturated fatty acids (PUFAs) in total fatty acids was little changed. Resistance of hepatocellular cancer cells to fatty metamorphosis and their susceptibility to necrosis induced by free radicals may be due to the paucity of the target PUFAs in their cell membrane fraction, resulting in low levels of lipid peroxides. Peroxidation of PUFAs might act as a “shock absorber” against free radical‐induced toxic cell death in normal cells.
- Published
- 1991
28. Appearance of a Carcinoid-like Pattern in Rat Hepatic Tumors Induced by 3′-Methyl-4-dimethyl -aminoazobenzene
- Author
-
Sanae Hirota, Yoshiaki Karaki, Toshio Saeki, Shuji Munakata, and Masao Fujimaki
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Silver ,Population ,Carcinoid Tumor ,Biology ,Stain ,Article ,law.invention ,p-Dimethylaminoazobenzene ,like pattern ,Liver Neoplasms, Experimental ,induced rat hepatic tumor ,law ,Argentaffin ,Internal medicine ,medicine ,Animals ,Endocrine system ,Cholangiofibrosis ,education ,Methyldimethylaminoazobenzene ,education.field_of_study ,Cell growth ,Carcinoid ,Pathophysiology ,Rats ,Endocrinology ,Oncology ,3′–MeDAB ,Electron microscope - Abstract
This study investigated the histological distribution of argyrophilic cells in experimental hepatic neoplasms, the number of these cells, and the proportion of neoplasms with such cells. Seventy 6–week–old male Donryu rats were given a 0.06% 3′–methyl–4–dimethyl–aminoazobenzene (3′–MeDAB) diet for 10 weeks, followed by an ordinary diet for an additional 10 weeks. Of the 70 rats, 50 were used for this investigation; 29 had hepatic tumors, 18 had cholangiofibrosis, and the other three had oval cell proliferation only. Hepatic tissues were stained with Grimelius and Fontana–Masson stains as well as routine hematoxylin–eosin stain. Argyrophilic cells were found in the hepatic neoplasms of 8 rats without argentaffin cells, while cholangiofibrosis was associated with argentaffin cells in almost all cases. Of the 8 rats with argyrophilic cells, three had an abundant population of these cells. The argyrophilic cells were found in areas of the neoplasms with a glandular, trabecular, tubular, or poorly differentiated pattern. Electron microscopy revealed that the neoplastic cells with a positive argyro–phil reaction contained small round electron–dense endocrine granules. In addition, in the areas of cholangiofibrosis, two different types of gut endocrine cells were present (G and EC cells). These results suggest that 3′–MeDAB might induce hepatic carcinoid under certain conditions, though we have yet to confirm the development of a pure hepatic carcinoid due to this substance.
- Published
- 1991
29. Low frequency of ras activation in 2-acetylaminofluorene- and 3′-methyl-4-(dimethylamino)azobenzene-induced rat hepatocellular carcinomas
- Author
-
Kimie Nomura, K. Ohtake, T. Kitagawa, Gang-Hong Lee, J. Liu, and H. Li
- Subjects
Male ,Cancer Research ,Carcinoma, Hepatocellular ,Transfection ,medicine.disease_cause ,Polymerase Chain Reaction ,chemistry.chemical_compound ,polycyclic compounds ,medicine ,Animals ,Transversion ,neoplasms ,Carcinogen ,Repetitive Sequences, Nucleic Acid ,Methyldimethylaminoazobenzene ,Chemistry ,Liver cell ,Liver Neoplasms ,Nucleic Acid Hybridization ,DNA ,2-Acetylaminofluorene ,HCCS ,medicine.disease ,Molecular biology ,digestive system diseases ,Rats ,Blotting, Southern ,Cell Transformation, Neoplastic ,Genes, ras ,Gene Expression Regulation ,Oncology ,Hepatocellular carcinoma ,Mutation ,Carcinogenesis - Abstract
Activation of ras protooncogenes in 11 2-acetylaminofluorene (AAF)-induced hepatocellular carcinomas (HCCs) or liver cell lines and 9 3′-methyl-(dimethylamino)azobenzene (3′-Me-DAB)-induced HCCs in rats was examined using the NIH3T3 cell transfection assay and oligonucleotide hybridization analysis. Only one cell line established from a AAF-treated rat liver demonstrated transforming activity with a point mutation and ATTA transversion at the second position of H-ras codon 61. The rates of ras activation were thus very low for both AAF-and 3′-Me-DAB-induced rat HCCs, the results thus extending and confirming the findings indicating that ras activation in rat HCCs induced by various type of carcinogens is infrequent.
- Published
- 1991
30. FOXA transcription factors determine the amplitude of glucocorticoid induction of tyrosine aminotransferase in mice
- Author
-
L. O. Bryzgalov, S. I. Ilnitskaya, and N. I. Ershov
- Subjects
medicine.medical_specialty ,animal structures ,Time Factors ,Biology ,o-Aminoazotoluene ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Tyrosine aminotransferase ,Internal medicine ,medicine ,Animals ,Transcription factor ,Glucocorticoids ,Tyrosine Transaminase ,Methyldimethylaminoazobenzene ,Mice, Inbred ICR ,fungi ,Liver Neoplasms ,Forkhead Transcription Factors ,General Medicine ,Enzyme Activation ,Endocrinology ,Liver ,embryonic structures ,Cancer research ,Glucocorticoid ,Icr mice ,medicine.drug ,Protein Binding - Abstract
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).
- Published
- 2008
31. Activation of constitutive androstane receptor under the effect of hepatocarcinogenic aminoazo dyes in mouse and rat liver
- Author
-
Mariya Y. Pakharukova, Tatyana I. Merkulova, V. I. Kaledin, Mariya A. Smetanina, V. F. Kobzev, and I. V. Romanova
- Subjects
O-Aminoazotoluene ,Male ,Coloring agents ,Receptors, Cytoplasmic and Nuclear ,Biology ,Ligands ,o-Aminoazotoluene ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Constitutive androstane receptor ,Animals ,Humans ,Rats, Wistar ,Coloring Agents ,Transcription factor ,Constitutive Androstane Receptor ,Methyldimethylaminoazobenzene ,Ligand ,Liver cell ,Liver Neoplasms ,General Medicine ,Rats ,Cytosol ,Biochemistry ,Rat liver ,Transcription Factors - Abstract
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.
- Published
- 2008
32. Analysis of cytological changes in hepatocytes from rats dosed with 3′-methyl-4-dimethylaminoazobenzene: initial response appears to involve cytokinesis of binucleated cells
- Author
-
M.D. Kelly, N.R. Pritchard, and J.A. Styles
- Subjects
Male ,Cancer Research ,Binucleated cells ,Administration, Oral ,Biology ,3 methyl 4 dimethylaminoazobenzene ,p-Dimethylaminoazobenzene ,medicine ,Animals ,Interphase ,Carcinogen ,Cell Nucleus ,Methyldimethylaminoazobenzene ,Ploidies ,DNA synthesis ,Cell Cycle ,Molecular biology ,Rats ,medicine.anatomical_structure ,Liver ,Oncology ,Biochemistry ,Hepatocyte ,Ploidy ,Cytokinesis ,After treatment - Abstract
The reduction in the ratio of tetraploid (4N + 2 × 2N) to diploid (2N) hepatocytes in the adult rat after treatment with the hepatocarcinogen 3′-methyl-4-dimethylaminoazobenzene (3′M) has been investigated. Analysis of isolated hepatocytes 18–28 days after treatment has confirmed that initially some of the 2 × 2N hepatocytes are converted into 2N cells by cytokinesis, and that there is no DNA synthesis during this process. Shortly afterwards non-polyploidizing growth commences by proliferation of some 2N cells.
- Published
- 1990
33. Lipid peroxidation in the liver of carcinogen-resistant rats
- Author
-
Taneaki Higashi, Yukiya Sakamoto, Noriko Tateishi, Mitsuya Hanatani, and Hanaa Hammad
- Subjects
Male ,Drug Resistance ,Biophysics ,Aldehyde dehydrogenase ,Mitochondria, Liver ,Biochemistry ,Lipid peroxidation ,chemistry.chemical_compound ,Endocrinology ,TBARS ,Animals ,Ferrous Compounds ,NADPH-Ferrihemoprotein Reductase ,Alcohol dehydrogenase ,Methyldimethylaminoazobenzene ,chemistry.chemical_classification ,Glutathione Peroxidase ,biology ,Superoxide Dismutase ,Glutathione peroxidase ,Alcohol Dehydrogenase ,Glutathione ,Aldehyde Dehydrogenase ,Catalase ,Thiobarbiturates ,Free radical scavenger ,Ascorbic acid ,Rats ,Liver ,chemistry ,Carcinogens ,Fatty Acids, Unsaturated ,Microsomes, Liver ,biology.protein ,Lipid Peroxidation ,NADP - Abstract
Recently, we developed a new strain of rats that exhibit marked resistance to the hepatotoxic and carcinogenic actions of 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB) and some other carcinogens. In this work, we compared lipid peroxidation in the liver of these carcinogen-resistant (R) rats and the parental Donryu strain rats that are sensitive (S) to hazardous actions of these carcinogens. The liver microsomal fractions of the R group contained less amounts of polyunsaturated fatty acids. Microsomal lipid peroxidation in the presence of exogenous NADPH was much lower in R rats than in S rats. Liver microsomes of R rats were much less active than those of S rats also in producing 4-hydroxynonenal, carbonyl compounds and conjugated diene. The hepatic contents of ascorbic acid, glutathione, α-tocopherol and coenzyme Q in the R rats were similar to those in S rats. The activities of the free radical scavenger enzymes, Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), in the two groups were also similar. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are both thought to function in disposal of these cytotoxic aldehydes. The liver microsomal and mitochondrial ALDH activities of the two groups were similar. The ADH activity of the liver cytosolic fraction of R rats was nearly twice that of S rats, as measured with 4-hydroxynonenal as substrate. The higher ADH activity may explain the decreased lipid peroxidation in R rats at least partly, if this enzyme is involved in lipid peroxidation.
- Published
- 1990
34. Studies on the hyperplastic responsiveness of binucleated rat hepatocytes
- Author
-
J.A. Styles, N.R. Pritchard, M.D. Kelly, and Alison Bybee
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Population ,p-Dimethylaminoazobenzene ,chemistry.chemical_compound ,Oral administration ,Internal medicine ,medicine ,Animals ,education ,Carcinogen ,Cell Nucleus ,Methyldimethylaminoazobenzene ,education.field_of_study ,Hyperplasia ,Cell Cycle ,General Medicine ,Cell cycle ,medicine.disease ,Rats ,Butyrates ,Endocrinology ,medicine.anatomical_structure ,Liver ,chemistry ,Nitrosamine ,Hepatocyte ,Clofenapate ,Corn oil - Abstract
Rats were dosed by gavage for 28 days with 25 mg/kg of 3'methyl-4-dimethylaminoazobenzene (3'M) followed by 4 days dosing with 0.5 ml/100 g corn oil. Livers from animals were taken at intervals during the 4 days of corn oil dosing and examined for S-phase activity and nuclearity. The treatment regime caused an increase in the proportion of diploid (2N) cells in the hepatocyte population, a decrease in the proportion of binucleated (2 x 2N) cells of approximately 50%, and induced an increase in cell replication. A second group of rats was dosed for 28 days with 0.5 ml/100 g corn oil followed by 4 days administration of 25 mg/kg methylclofenapate (MCP). Analysis of hepatocytes taken during the MCP treatment revealed that there was acute hyperplasia, involving mainly the 2 x 2N hepatocytes, resulting in a reduction of approximately 50% of the 2 x 2N cells and an accompanying increase in the proportion of 4N cells. When a third group was given 3'M for 28 days followed by 4 days administration of MCP, there was, at the outset of MCP dosing, a hepatocyte population typical of 3'M dosed animals, with an elevated proportion of 2N cells and a 2 x 2N fraction that was reduced to approximately 50% of control levels. During the 4 days of MCP dosing there was a wave of hyperplasia involving S-phase activity in the remaining 2 x 2N hepatocytes. The proportion of 2 x 2N cells decreased further during this period and there was a concomitant increase in 4N cells. The 2N fraction, already elevated, was not further affected. These results indicate that both genotoxic and non-genotoxic hepatocarcinogens induce acute changes in the rat hepatocyte population that involve 2 x 2N cells, and that the effects appear to involve separate sub-populations of 2 x 2N hepatocytes.
- Published
- 1990
35. Bile canaliclar alterations in hepatocyte nodules induced by 3'-methyl-4-dimethylaminoazobenzene in the rat: morphological clues on their pathogenesis and relevainice to the neoplastic process
- Author
-
Jean-Yves Scoazec, Gérard Feldmann, and Nadia Hassan
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Biology ,Bone canaliculus ,digestive system ,Malignant transformation ,Pathogenesis ,Liver Neoplasms, Experimental ,medicine ,Animals ,Cytoskeleton ,Methyldimethylaminoazobenzene ,Bile Canaliculi ,Nodule (medicine) ,General Medicine ,Phenotype ,Rats, Inbred F344 ,Rats ,Microscopy, Electron ,Bile Ducts, Intrahepatic ,medicine.anatomical_structure ,Liver ,Hepatocyte ,Ultrastructure ,medicine.symptom ,Precancerous Conditions - Abstract
One characteristic change of hepatocyte plasma membrane in chemically induced nodules of rat liver is the spreading over on the whole cell surface of proteins normally associated with the canalicular domain. However, these proteins may present comparable altered patterns of membrane distribution in non-neoplastic situations, e.g. in cholestatic states. Consequently, the significance of an abnormal membrane distribution of canalicular proteins in hepatocyte nodules and its possible relevance to the neoplastic process remain to be clarified. We have therefore performed an ultrastructural study of bile canalicular alterations in the hepatocyte nodules induced by 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), in an attempt to gain some insight on their pathogenesis. We actually observed frequent bile canalicular changes in hepatocyte nodules from 10 to 16 weeks after the beginning of 3'-Me-DAB administration. These changes correlated with the rearrangements in hepatocyte architecture occurring at this stage of the neoplastic process, corresponding to the so-called pseudo-acinar structures and disorganized plates. In pseudo-acinar structures, hepatocytes were arranged in a tubular manner around dilated bile canaliculi. In this situation, bile canaliculi have lost many of their normal features and closely resemble ductular lumina. In disorganized plates, hepatocyte plates were thickened and irregularly branched. In this situation, bile canaliculi presented striking deviations from the normal, including: (i) dilatation and distortion, (ii) lesions of canalicular membrane (loss of microvilli, formation of blebs) and (iii) alterations in the pericanalicular cytoskeletal network. Most of these morphological abnormalities closely resembled those found in cholestatic states. Two pathogenetic mechanisms may be postulated to explain the cholestatic-like effect of 3'-Me-DAB: (i) a direct cellular injury caused by the carcinogen or (ii) an indirect consequence of the tissular rearrangements characteristic of disorganized plates. Our morphological results suggest that the phenotypic alterations of bile canaliculi induced by 3'-Me-DAB are not specific for the neoplastic process. They are likely to correspond to an impairment in the biogenesis of the canalicular membrane and/or in the maintenance of its integrity.
- Published
- 1990
36. Retinyl acetate inhibition of 3'-methyl-4-dimethyl-aminoazobenzene induced hepatic neoplasia
- Author
-
Larry D. Smith, Victoria L. Reed, and Donald O. Mack
- Subjects
Retinyl Esters ,medicine.medical_specialty ,Time Factors ,Dietary factors ,Retinyl acetate ,Biochemistry ,p-Dimethylaminoazobenzene ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Vitamin A ,Tumor marker ,Methyldimethylaminoazobenzene ,Chemistry ,Adenylosuccinate Lyase ,Rats, Inbred Strains ,gamma-Glutamyltransferase ,N-Acetylneuraminic Acid ,Rats ,Endocrinology ,Liver ,Sialic Acids ,Female ,Diterpenes ,Precancerous Conditions - Abstract
1. 1. Retinyl acetate protected female rats from the hepatocarcinogenic effect of 0.06% 3'-Me-DAB up to 18 weeks. 2. 2. The net effect of retinyl acetate was to retard, not prevent, the action of the hepatocarcinogen since the protection broke down prior to the 30 week time point. 3. 3. The observed elevation of serum LSA by retinyl acetate was unexpected and suggested that some of the difficulties found in its use as a tumor marker may be due to dietary factors. 4. 4. The time necessary for development of preneoplastic lesions in the rats fed 0.01% 3'-Me-DAB was 71 vs 8 weeks for those fed 0.06% 3'-Me-DAB. 5. 5. The effect of retinyl acetate on the lower level of 3'-Me-DAB was to prevent formation of nodules through 71 weeks by which time the unprotected rats fed 0.01% 3'-Me-DAB alone had extensive hepatic nodular development.
- Published
- 1990
37. Expression of retinoid X receptor alpha is decreased in 3'-methyl-4-dimethylaminoazobenzene-induced hepatocellular carcinoma in rats
- Author
-
Nobuhiro, Ando, Masahito, Shimizu, Masataka, Okuno, Rie, Matsushima-Nishiwaki, Hisashi, Tsurumi, Takuji, Tanaka, and Hisataka, Moriwaki
- Subjects
Adenoma ,Cell Nucleus ,Male ,Methyldimethylaminoazobenzene ,Carcinoma, Hepatocellular ,Retinoid X Receptor alpha ,Receptors, Retinoic Acid ,Reverse Transcriptase Polymerase Chain Reaction ,Retinoic Acid Receptor alpha ,Blotting, Western ,Rats, Inbred F344 ,Rats ,Gene Expression Regulation, Neoplastic ,Immunoenzyme Techniques ,Liver Neoplasms, Experimental ,Glutathione S-Transferase pi ,Animals ,Cyclin D1 ,RNA, Messenger ,beta Catenin - Abstract
The identification of the specific molecular targets, which underlie liver carcinogenesis is essential for the establishment of an effective strategy for the prevention and/or treatment of hepatocellular carcinomas (HCCs). We previously found that a malfunction of RXRalpha due to its aberrant phosphorylation was associated with the development of HCCs. However, it has remained unclear whether the abnormalities in the expression of RXRalpha or the other retinoid receptors play a role in the early stage of liver carcinogenesis. The present study was designed to determine whether alterations in the expression of RXRalpha and the other retinoid receptors RARalpha and RARbeta are involved in hepatocarcinogenesis using a 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB)-induced rat liver carcinogenesis model. We found that immunohistochemical expression of RXRalpha was decreased in liver cell tumors (HCCs and adenoma) and glutathione S-transferase placental form (GST-P)-positive foci, which is a precancerous lesion of HCC, when compared with the non-cancerous tissues. Western blot and RT-PCR analyses revealed a progressive decrease in the expression levels of RXRalpha, RARalpha, and RARbeta proteins and their mRNAs in 3'-MeDAB-induced HCCs and their surrounding tissues, when compared with the normal liver tissues from the control group. Moreover, the expression level of beta-catenin, the heterodimeric partner for both RXRalpha and RARalpha, was immunohistochemically observed in the cytoplasm and, in some cases, in the nucleus of HCC cells. The nuclear expression of cyclin D1, the downstream target molecule of beta-catenin, was also increased in HCC cells when compared with their adjacent normal appearing tissues. Our findings suggest that loss of retinoid receptors, especially RXRalpha, plays a critical role in the chemically-induced rat liver carcinogenesis and this might be associated with the activation of beta-catenin-related signaling pathway.
- Published
- 2007
38. Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TGF-alpha-expressing oval-like cells and activated hepatic stellate cells
- Author
-
Hisashi Tsurumi, Takuji Tanaka, Masataka Kagawa, Rikako Suzuki, Soichi Kojima, Naoto Ishibashi, Yukihiko Takano, Scott L. Friedman, Megumi Yamamoto, Hiroyuki Kohno, Rie Matsushima-Nishiwaki, Hisataka Moriwaki, Masataka Okuno, Manabu Hashimoto, and Tetsuro Sano
- Subjects
Adenoma ,Male ,Cancer Research ,medicine.medical_specialty ,TGF alpha ,Time Factors ,medicine.drug_class ,Medicine (miscellaneous) ,Antineoplastic Agents ,Tretinoin ,Biology ,medicine.disease_cause ,Retinoids ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Retinoid ,Progenitor cell ,Methyldimethylaminoazobenzene ,Nutrition and Dietetics ,Dose-Response Relationship, Drug ,Cell growth ,Reverse Transcriptase Polymerase Chain Reaction ,Carcinoma ,Transforming Growth Factor alpha ,medicine.disease ,Fibrosis ,Actins ,Rats, Inbred F344 ,Rats ,Disease Models, Animal ,Endocrinology ,Oncology ,Liver ,Hepatocellular carcinoma ,Hepatic stellate cell ,Disease Progression ,Carcinogenesis ,Transforming growth factor - Abstract
We investigated the preventive effects of a synthetic acyclic retinoid, NIK-333, on the early and late events of hepatocarcinogenesis in male F344 rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB). NIK-333 was administered once a day on consecutive days at a dose of 10, 40, or 80 mg/kg body weight along with the supplementation with 3'-MeDAB-containing diet for 16 wk. Animals from each group were sacrificed at 4 and 16 wk after the commencement of the experiment to determine the effect of NIK-333 on the early and late stages of carcinogenesis, respectively. NIK-333 suppressed the emergence of both oval-like cells expressing transforming growth factor (TGF)-alpha, putative progenitors of hepatocellular carcinoma (HCC), and activated hepatic stellate cells, major matrix-producing cells of the liver, in the early stage and inhibited the incidence of HCC in the late phase. These results suggest that NIK-333 is a promising drug for the chemoprevention of HCC by uniquely suppressing the early events of hepatocarcinogenesis, that is, development of both oval-like cells and fibrogenesis.
- Published
- 2005
39. Role of resistant Drh1 locus in chemical carcinogen-induced hepatocarcinogenesis in rats: analysis with a speed congenic strain
- Author
-
Hiroshi Hiai, Ken Higashi, and Hongbo Liu
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Quantitative Trait Loci ,Congenic ,Administration, Oral ,Apoptosis ,Biology ,medicine.disease_cause ,digestive system ,Liver Neoplasms, Experimental ,Fibrosis ,medicine ,In Situ Nick-End Labeling ,Animals ,Genetic Predisposition to Disease ,Carcinogen ,Methyldimethylaminoazobenzene ,TUNEL assay ,Reverse Transcriptase Polymerase Chain Reaction ,Liver cell ,Gene Expression Profiling ,Cell Cycle ,General Medicine ,respiratory system ,medicine.disease ,Molecular biology ,digestive system diseases ,Rats, Inbred F344 ,Rats ,surgical procedures, operative ,Cell Transformation, Neoplastic ,Oncology ,Carcinogens ,Hepatocytes ,Liver cancer ,Carcinogenesis - Abstract
The DRH is an inbred rat strain established by selective mating of the 3'-Me-DAB resistant progeny of closed colony Donryu rats over 20 generations. Genetic analysis shows that two semidominant QTLs, Drh1 and Drh2, are responsible for strong resistance to chemical-induced hepatocarcinogenesis in DRH strain rats. To evaluate the effect of the single Drh1 locus on various stages of liver carcinogenesis, we constructed a speed congenic strain DRH.F344-Drh1 by transferring a susceptible Drh1 allele of F344 to DRH rats by marker-assisted backcrossing. The DRH.F344-Drh1 rats had a approximately 43 cM segment of chromosome 1 bearing Drh1 but the Drh2 was of the DRH allele. After oral administration of 3'-Me-DAB for 8 weeks, DRH.F344-Drh1 had as many enzyme altered foci as F344, whereas the quantitative parameters of fibrosis, enzyme altered foci, GST-P expression and proliferation of liver cells in DRH.F344-Drh1 rats were intermediate between F344 and DRH. In the liver of carcinogen-fed DRH rats, there was intensive apoptosis as detected by TUNEL stain, but not in the liver of F344 and DRH.F344-Drh1 rats. Injection of lead nitrate (100 micromol/kgB.W) induced a wave of liver cell proliferation, as seen by BrdU uptake within a few days in F344 and DRH.F344-Drh1 rats, but not in DRH rats. Instead, there were numerous TUNEL-positive nuclei in the DRH liver after lead nitrate injection. Apparently, the hepatocytes were removed by apoptosis during transition from G0 to G1. The major role of Drh1 is effective removal of the hepatocytes newly recruited to proliferate after chemical injury. Resistance to preneoplastic lesions in DRH rats may well be based on similar mechanism.
- Published
- 2005
40. The unknown nuclear protein that decreases HNF3 activity ensures species specificity of action of hepatocarcinogenic amino azo dyes
- Author
-
Tatyana I. Merkulova, V. I. Kaledin, K. Yu. Kropachev, M. Yu. Pakharukova, L. O. Bryzgalov, and V. F. Kobzev
- Subjects
Hepatocyte Nuclear Factor 3-alpha ,Male ,Methyldimethylaminoazobenzene ,Stereochemistry ,Chemistry ,Biophysics ,Down-Regulation ,Nuclear Proteins ,General Chemistry ,General Medicine ,Biochemistry ,o-Aminoazotoluene ,Rats ,DNA-Binding Proteins ,Mice ,Action (philosophy) ,Liver ,Species Specificity ,Animals ,Diethylnitrosamine ,Nuclear protein ,Coloring Agents ,Transcription Factors - Published
- 2004
41. Genetic resistance to chemical hepatocarcinogenesis in the DRH rat strain
- Author
-
Ken, Higashi, Ayumi, Denda, Taneaki, Higashi, and Hiroshi, Hiai
- Subjects
Methyldimethylaminoazobenzene ,DNA Adducts ,Carcinoma, Hepatocellular ,Liver Neoplasms, Experimental ,Hepatocytes ,Animals ,Hepatectomy ,Rats, Inbred Strains ,Immunity, Innate ,Rats - Abstract
The carcinogen-resistant inbred rat strain DRH established from closed-colony Donryu rats by use of selective brother-sister mating over 20 generations under continuous feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) maintains a highly resistant phenotype without carcinogen exposure for many years. We reported that the clonal expansion of preneoplastic glutathione S-transferase-P(GST-P)-positive foci induced by 3'-Me-DAB was less extensive in the liver of DRH rats than in the liver of susceptible strains, such as Donryu and F344, although levels of DNA adducts were comparable among these rats. Comparative studies of the events after initiation indicate that DRH rats are constitutionally less prone to cellular damage caused by continuous administration of 3'-Me-DAB than are parental Donryu rats. Consequently, the reduced growth response of the liver during the promotion stage may contribute to the low susceptibility to development of liver tumors. Genetic analysis of (F344 x DRH)F2 rats identified two quantitative trait loci, Drh1 on chromosome 1 and Drh2 on chromosome 4, which provide resistance to the development of GST-P-positive preneoplastic foci induced by 3'-Me-DAB during the early stage of its administration. The resistance to progression to hepatocellular carcinoma is affected solely by Drh2. These observations indicate that at least two genetic loci are critically involved in the steps leading to chemical hepatocarcinogenesis. The DRH rat is a useful experimental model with which to study genetic susceptibility and resistance to chemically induced liver cancers.
- Published
- 2004
42. Erythropoietin/Erythropoietin-receptor system as an angiogenic factor in chemically induced murine hepatic tumors
- Author
-
Osamu Maenishi, Kiyoshi Nakamatsu, Yasumasa Nishimura, Minoru Suzuki, Shuichi Kanamori, and Yoshiko Yasuda
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Cirrhosis ,Endothelium ,Angiogenesis ,Radioimmunoassay ,Liver Cirrhosis, Experimental ,Liver Neoplasms, Experimental ,Surgical oncology ,hemic and lymphatic diseases ,Internal medicine ,Receptors, Erythropoietin ,medicine ,Animals ,Rats, Wistar ,Receptor ,Erythropoietin ,Methyldimethylaminoazobenzene ,Neovascularization, Pathologic ,business.industry ,Hematology ,General Medicine ,medicine.disease ,Immunohistochemistry ,Capillaries ,Rats ,Erythropoietin receptor ,Endocrinology ,medicine.anatomical_structure ,Liver ,Oncology ,Surgery ,business ,medicine.drug - Abstract
To clarify the role of erythropoietin (Epo) in hepatic tumor angiogenesis, expression of Epo and its receptor (Epo-R) and content of Epo were investigated in murine chemically induced hepatic tumors.To induce hepatic tumors and cirrhosis, diaminobenzidine was administered to Wistar rats for 5 months. In total, 30 hepatic tumors of greater than 3 mm in diameter were induced in 12 rats. The 30 hepatic tumors were resected with the surrounding hepatic tissues. The Epo content was measured by a radioimmunoassay (RIA) method. The number of tumor vessels in a definite area was counted in 100 areas of each tumor. To demonstrate the expression of Epo-R in tumors or surrounding liver tissues, immunohistochemical staining for Epo-R was performed.The Epo content of tumors ranged from 6.1 to 97.8 mU/ml, with a median of 21.8 mU/ml, which was significantly higher than that of the cirrhotic tissues adjacent to the tumors. Epo was not detectable in the normal or cirrhotic liver tissues without tumors. A significant correlation between Epo content and vascular density was noted in the 30 hepatic tumors (correlation coefficient, 0.480; P = 0.01). Immunoreactive Epo-R was detectable in the endothelium of intervening vessels of all hepatic tumors examined.The Epo/Epo-R system is related to the angiogenesis of murine hepatic tumors. To clarify the role of erythropoietin (Epo) in hepatic tumor angiogenesis, expression of Epo and its receptor (Epo-R) and content of Epo were investigated in murine chemically induced hepatic tumors.
- Published
- 2004
43. Modulation of genetic resistance to hepatocarcinogenesis in DRH rats by partial hepatectomy
- Author
-
Hongbo Liu, Hiroshi Hiai, Kazumi Nobumoto, Yoshihiro Yamada, and Ken Higashi
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Cell division ,medicine.medical_treatment ,Biology ,Liver Neoplasms, Experimental ,Internal medicine ,medicine ,Animals ,Hepatectomy ,Genetic Predisposition to Disease ,Allele ,Carcinogen ,Methyldimethylaminoazobenzene ,Cell growth ,Rats, Inbred Strains ,medicine.disease ,Rats, Inbred F344 ,Rats ,Endocrinology ,Oncology ,Hepatocellular carcinoma ,Allelic Imbalance ,Carcinogens ,Liver cancer ,Cell Division - Abstract
The DRH is an inbred rat strain highly resistant to chemically induced hepatocarcinogenesis. Two clusters of resistance loci Drh1 and Drh2 on chromosome 1 and 4 yield strong resistance to the formation of enzyme-altered foci and their progression. To evaluate the effect of enhanced cell proliferation in the progression stage, a partial hepatectomy (PH) was carried out in (DRH x F344)F1 rats 8 weeks after the start of 3'-Me-DAB administration. The incidence of liver cancer in the PH-F1 rats was equivalent to that in the F344 rats, although the number of tumors per rat was much lower. In contrast, the F1 rats without PH rarely developed cancers. Such modulation was not due to the loss of the resistance allele, since none of 18 hepatocellular carcinomas in PH-F1 rats showed allelic imbalance at Drhl and Drh2.
- Published
- 2003
44. [Quantitative analysis of p53 and related genes mRNA in rat hepatocarcinogenesis induced by 3'-Me-DAB]
- Author
-
Yan, Fu, Wei-Guo, Deng, Yu-Lin, Li, and Toshihiro, Sugiyama
- Subjects
Male ,Methyldimethylaminoazobenzene ,Genes, p53 ,Actins ,Rats, Inbred F344 ,Rats ,Liver Neoplasms, Experimental ,Liver ,Albumins ,Animals ,RNA, Messenger ,alpha-Fetoproteins ,Tumor Suppressor Protein p53 ,Glutathione Transferase - Abstract
p53 gene mutations and abnormal expression of p53 in hepatocarcinoma have been reported, but alteration in mRNA level is not yet understood. In order to find out the alteration in mRNA levels of p53, glutathione S-transferase P (GST-P), alpha-fetoprotein (AFP), and albumin in genesis, developing, and prognosis of hepatocarcinoma, quantitative analysis of mRNA levels of p53, GST-P, AFP, and albumin in prehepatocarcinoma and hepatocarcinoma foci was performed.During hepatocarcinogenesis of F344 rat induced by 3'-methyl-4-dimethylamino-azobenzene (3'-Me-DAB), the levels of these mRNAs were quantitatively analyzed by LightCycler V3 System real-time RT-PCR after capturing accurately micro-foci in prehepatocarcinoma and hepato-carcinoma of rats with laser capture microdissection (LCM).At the 6th, 12th and 24th experiment weeks, the p53 mRNA levels in all of prehepatocarcinoma foci were markedly higher than those in the adjacent normal tissues (all of Por = 0.001), and gradually decreased from the 6th week to the 24th week (P0.01). The content of p53 mRNA in hepatocarcinoma foci was higher than that in normal tissue (P = 0.028 and 0.013), but lower than that in prehepatocarcinoma foci. At 24th weeks, the sections of livers exhibited intensive immunostaining of p53 protein in prehepatocarcinoma and hepatocarcinoma foci. At any time-point of experiment, GST-P mRNA levels in prehepatocarcinoma foci were significantly higher than those in the adjacent normal liver tissue and hepatocarcinoma foci (all of P0.001). The concentration of AFP mRNA was the highest (P0.001) and that of albumin mRNA was the lowest (P0.01) in hepatocarcinoma foci as compared with adjacent normal tissue and prehepatocarcinoma foci. The GST-P protein and AFP protein were expressed strongly in prehepatocarcinoma and hepatocarcinoma foci, respectively.GST-P and AFP mRNA overexpressed in prehepatocarcinoma and hepatocarcinoma foci respectively will be profitable markers for diagnosis during hepatocarcinogenesis. The p53 mRNA highly expressed at early stage of prehepatocarcinoma and hepatocarcinoma, but the increasing concentration of p53 protein was found at later stage.
- Published
- 2003
45. [The characteristics and significance of oncogenes expression in oval cells cultivated in vitro]
- Author
-
L, Xue, J, Wen, and G, Zhao
- Subjects
Methyldimethylaminoazobenzene ,Mice, Inbred BALB C ,Genes, myc ,Gene Expression ,Rats ,Rats, Sprague-Dawley ,Mice ,Cell Transformation, Neoplastic ,Genes, ras ,Liver Neoplasms, Experimental ,Liver ,Animals ,Cells, Cultured ,Neoplasm Transplantation - Abstract
To study the relationship between expression characteristics of oncogenes and transformation of the oval cells cultivated in vitro.Liver oval cells of SD rats induced by feeding with chemical carcinogen 3'-Me-DAB for four weeks were isolated using Percoll density gradient centrifugation. The cells were continuously cultivated in vitro and the dynamic characteristics of Ha-ras, Ki-ras and c-myc genes expression in the oval cells were detected using RNA-DNA slot blot hybridization.During long term cultivation, the population doubling time of the cells became shorter and the percentage of aneuploidy chromosomes and colonies grown in soft agar increased. Ha-ras Ki-ras and c-myc were synchronically expressed in the oval cells from different passages.The activation and synergistic over-expression of Ha-ras Ki-ras and c-myc had an important role in the proliferation and transformation of oval cells in vitro.
- Published
- 2001
46. Analyses of oxidative DNA damage and its repair activity in the livers of 3'-methyl-4-dimethylaminoazobenzene-treated rodents
- Author
-
Yuko Ootsuyama, Hiroshi Kasai, Yosuke Tsurudome, Ken Higashi, Takeshi Hirano, Rie Kido, and Akinori Sakai
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Guanine ,Time Factors ,Rodent ,DNA Repair ,Ratón ,medicine.disease_cause ,Article ,Oxidative dna damage ,3 methyl 4 dimethylaminoazobenzene ,chemistry.chemical_compound ,Mice ,Liver Neoplasms, Experimental ,biology.animal ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Coloring Agents ,N-Glycosyl Hydrolases ,Carcinogen ,Methyldimethylaminoazobenzene ,biology ,8‐Hydroxyguanine ,Reverse Transcriptase Polymerase Chain Reaction ,DNA ,Rats ,8‐Oxoguanine DNA glycosylase 1 ,Oxidative Stress ,Endocrinology ,Oncology ,Biochemistry ,chemistry ,DNA-Formamidopyrimidine Glycosylase ,Liver ,Carcinogens ,Disease Susceptibility ,Carcinogenesis ,Oxidative stress ,DNA Damage ,3′‐MeDAB ,Carcinogenresistant DRH rat - Abstract
We measured the levels of 8‐hydroxyguanine (8‐OH‐Gua) and its repair activity in the livers of the Donryu rat, the carcinogen‐resistant DRH rat, and the ddy mouse, which were fed a 0.06% 3′‐ methyl‐4‐dimethylaminoazobenzene (3′‐MeDAB)‐containing diet. In a short‐term rat experiment (maximum 2 months), 3′‐MeDAB did not increase the 8‐OH‐Gua levels in the livers of the two rat strains, although it significantly increased the repair activity in only the Donryu rat liver at 1 and 2 months. After long‐term 3′‐MeDAB administration to the ddy mouse (8 months), the levels of 8‐OH‐Gua and its repair activity were increased in the liver by 3.6‐fold and 1.6‐fold, respectively. These experiments suggest that 3′‐MeDAB increases 8‐OH‐Gua generation in rodent liver DNA and the 8‐OH‐Gua repair assay is a reliable marker of cellular oxidative stress induced by carcinogens.
- Published
- 2000
47. Changes in Number of α-Adrenergic Receptor Subtypes in Hepatocytes from Rats Fed 3′-Methyl-4-dimethylaminoazobenzene
- Author
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Kenichi Miyamoto, Ryozo Koshiura, Masaaki Nomura, Keiko Kohei, and Fujiko Sanae
- Subjects
Cancer Research ,medicine.medical_specialty ,Period (gene) ,Alpha (ethology) ,Biology ,Clonidine ,3 methyl 4 dimethylaminoazobenzene ,p-Dimethylaminoazobenzene ,Internal medicine ,medicine ,Prazosin ,Animals ,Receptor ,Carcinogen ,Methyldimethylaminoazobenzene ,Receptors, Adrenergic, alpha ,Rats ,Endocrinology ,medicine.anatomical_structure ,Liver ,Oncology ,Hepatocyte ,Female ,Rapid Communication ,medicine.drug - Abstract
Changes in numbers of alpha 1- and alpha 2-adrenergic receptors in the plasma membranes of hepatocytes from female Donryu rats given feed containing 0.06% of the carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), were examined. alpha 1-Adrenergic receptors, measured in terms of [3H]prazosin binding, decreased to half of the control 2 weeks after the start of this diet, then gradually decreased for the next 22 weeks. alpha 2-Adrenergic receptors, measured in terms of [3H]clonidine binding, transiently increased 3-fold over the control at 2 weeks. These changes in the early period of the 3'-MeDAB diet intake may be related to hepatocarcinogenesis.
- Published
- 1990
48. Hepatocyte growth factor stimulates DNA synthesis in rat preneoplastic hepatocytes but not in liver carcinoma cells
- Author
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Jun Hiramoto, Kazuo Nagayama, Akihiro Furusaka, Masaaki Takahashi, Teruji Tanaka, Keigo Shirahama, Hisataka Ogasawara, Tetsuya Nakada, and Satoshi Hiyane
- Subjects
Male ,medicine.medical_specialty ,Biology ,medicine.disease_cause ,chemistry.chemical_compound ,Liver Neoplasms, Experimental ,Western blot ,In vivo ,Internal medicine ,medicine ,Carcinoma ,Animals ,Humans ,Phosphorylation ,Methyldimethylaminoazobenzene ,Hepatology ,DNA synthesis ,medicine.diagnostic_test ,Hepatocyte Growth Factor ,Gastroenterology ,Tyrosine phosphorylation ,DNA ,Proto-Oncogene Proteins c-met ,medicine.disease ,Immunohistochemistry ,Rats ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Bromodeoxyuridine ,Hepatocyte ,Type C Phospholipases ,Cancer research ,Tyrosine ,Hepatocyte growth factor ,Carcinogenesis ,Precancerous Conditions ,medicine.drug - Abstract
Background & Aims: It is not well clarified whether hepatocyte growth factor (HGF) stimulates the growth of preneoplastic hepatocytes and liver carcinoma cells in vivo. The effect of HGF on in vivo DNA synthesis in these cells and also its effect on tyrosine phosphorylation of the HGF receptor protein (c-Met) in liver carcinoma were examined. Methods: Lesions were induced in rats using 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). The rats were given intravenous recombinant human HGF or vehicle, and DNA synthesis was assessed by the 5-bromo-2'-deoxyuridine labeling index. Tyrosine phosphorylation of c-Met by HGF was analyzed by Western blot. Results: The labeling indices were significantly higher in the HGF group than in the vehicle control group in altered foci and hyperplastic nodules (preneoplastic hepatic lesions). No significant differences in the labeling indices were observed between the two groups with carcinoma. Tyrosine phosphorylation of c-Met in carcinoma cells was unaffected by HGF administration. Conclusions: HGF promotes the growth of preneoplastic hepatocytes but does not affect the growth of liver carcinoma cells in 3'-Me-DAB–treated rats. GASTROENTEROLOGY 1998;114:775-781
- Published
- 1998
49. High expression of alpha-1-6 fucosyltransferase during rat hepatocarcinogenesis
- Author
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K, Noda, E, Miyoshi, N, Uozumi, C X, Gao, K, Suzuki, N, Hayashi, M, Hori, and N, Taniguchi
- Subjects
Methyldimethylaminoazobenzene ,Rats, Sprague-Dawley ,Aging ,Liver Neoplasms, Experimental ,Carbohydrate Sequence ,Liver ,Molecular Sequence Data ,Carcinogens ,Animals ,Gene Expression ,RNA, Messenger ,Fucosyltransferases ,Rats - Abstract
Alpha-1-6 fucosylated alpha-fetoprotein (AFP) is known to be elevated in patients with primary hepatoma and has been suggested as being useful as an early indicator and predictor of the poor prognosis for hepatoma. Although GDP-L-fucosyl-N-acetyl-beta-D-glucosaminide alpha-1-6 fucosyltransferase (alpha-1-6 FucT), is the key enzyme involved in alpha-1-6 fucosylation of AFP, when and how the expression of alpha-1-6 FucT is enhanced during hepatocarcinogenesis is unknown. Recently, we established a convenient assay method for this enzyme and were successful in the purification and cDNA cloning of alpha-1-6 FucT from human gastric cancer, as well as from porcine brain. In the present study, levels of alpha-1-6 FucT activity and mRNA expression have been determined during hepatocarcinogenesis in LEC rats which spontaneously develop hereditary hepatitis and hepatoma. The fetal liver contained the highest enzymatic activity, which tended to increase in inverse proportion to gestation. The enzymatic activity was significantly increased in hepatoma tissues as compared with uninvolved adjacent tissues. Northern-blot analysis revealed high expression of alpha-1-6 FucT mRNA in hepatoma tissues, whereas the expression was fairly low in normal, hepatitis and uninvolved adjacent liver tissues. While the fetal liver had the highest enzymatic activity, the expression of alpha-1-6 FucT mRNA was low, suggesting that another alpha-1-6 FucT is induced in fetal liver or that post-translational modification occurs. High expression of alpha-1-6 FucT was also observed in 3'-MeDAB-induced rat hepatomas and some rat hepatoma cell lines. Collectively, alpha-1-6 FucT was strongly enhanced from an early stage of hepatocarcinogenesis and was maintained at a high level in rat hepatomas.
- Published
- 1998
50. [Establishment of an estrogen receptor positive 3'-methyl-4-dimethylaminoazobenzene induced hepatoma cell line of rat and investigation of hormonal therapy]
- Author
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H, Kameda
- Subjects
Male ,Methyldimethylaminoazobenzene ,Carcinoma, Hepatocellular ,Estradiol ,Liver Neoplasms ,Estrogen Antagonists ,Rats ,Tamoxifen ,Receptors, Estrogen ,Tumor Cells, Cultured ,Animals ,Castration ,Rats, Wistar ,Cell Division - Abstract
An estrogen receptor (ER) positive cell line was newly established from a Wistar King Aptekman (WKA) rat, 3'-methyl-4-dimethylaminoazobenzene (DAB) induced hepatoma cell lines. The impact of hormonal therapy on cell growth was investigated. This cell line produced alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and ferritin in the conditioned medium. Progesterone receptors (PgR) were positive but androgen receptors (AR) were not detected. This cell line's doubling time was about 10.5 hours in a routine medium and 12.2 hours in the endogenous estrogen removed medium (exponential phase). The morphological features of the cell were of a hepatocellular type as observed by light microscopy. The modal chromosome number was 56 and the DNA ploidy pattern was aneuploid as observed by flow cytometry. The addition of 17 beta-estradiol (E2) did not increase cell growth but tamoxifen (TAM) in vitro inhibited cell growth in the lag phase. Surgical castration or oral administration of E2 or TAM in vivo inhibited tumor growth in the early phase. There were no additional effects between surgical castration and the administration of E2. Surgical castration plus the administration of TAM were not effective when combined. The administration of TAM caused the physiological effect of castration eg., diminished blood testosterone level same as E2 administration. TAM also decreased the maximal binding capacity (Bmax) of ER. A morphological change to the cholangiocell carcinoma type was noticed. These results that this cell line was ER dependent in the early phase of tumor growth.
- Published
- 1996
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