Increased nucleoside triphosphatase activity of rat liver nuclear envelope is associated with hepatocarcinogen exposure (original) (raw)
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Cancer research, 1982
Technical modifications of the quantitative determination of unscheduled DNA synthesis in cultured hepatocytes are described which allow for the rapid identification of potentially carcinogenic chemicals on a large-scale screening basis. The test is based on the biochemical quantification of [methyl-3H]thymidine incorporation into DNA in the presence of hydroxyurea following isolation of nuclei from hepatocytes treated with the agent under study. This procedure ("nuclei procedure") eliminates most of the background radioactivity which otherwise obscures the stimulation of DNA repair synthesis by agents that induce a relatively weak response. By combining the nuclei procedure with a double-labeling technique, test results can be obtained within a few hr after exposure of hepatocytes to the test agents. A test series involving 41 agents confirmed the reliability of the nuclei procedure for the assay of DNA repair synthesis. In addition, chemicals which had yielded conflictin...
Environmental Health Perspectives, 1990
This paper is the third chronological supplement to the Carcinogenic Potency Database that first appeared in this journal in 1984 (1-4). We report here results of carcinogenesis bioassays published in . This supplement includes results of 337 long-term, chronic experiments of 121 compounds, and reports the same information about each experiment in the same plot format as the earlier papers, e.g., the species and strain of animal, the route and duration of compound administration, dose level, and other aspects of experimental protocol, histopathology, and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, opinion of the author about carcinogenicity, and literature citation. The reader needs to refer to the 1984 publication for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The four plots of the database are to be used together as results published earlier are not repeated. In all, the four plots include results for approximately 4000 experiments on 1050 chemicals. Appendix 14 of this paper is an alphabetical index to all chemicals in the database and indicates which plot(s) each chemical appears in. A combined plot of all results from the four separate papers, that is ordered alphabetically by chemical, is available from the first author, in printed form or on computer tape or diskette.
Zeitschrift f�r Krebsforschung und Klinische Onkologie, 1976
Abteilung fiir Cytopathologie, ]nstitut ftir Experimentelle Pathologic am Deutschen Krebsforschungszentrum, D-6900 Heidelberg, Federal Republic of Germany * This investigation was supported by a research visitors' grant of Deutsches Krebsforschungszentrum Heidelberg (Germany) and by Fonds de la Recherche Scientifique M~dicale (Belgium) 54 H.S. Taper and P. Bannasch Histochemische Korrelation von Giykogen, Nucleins~iuren und Nucleasen in praeneoplastischen und neoplastischen L~isionen der Rattenleber nach kurzfristiger Gabe yon N-Nitrosomorpholin Zusammenfassung. Die orale Gabe des Carcinogens N-Nitrosomorpholin (12 mg ad 100 ml Trinkwasser) an m~innliche Ratten ffihrt innerhalb yon 7 Wochen zu ausgepr~igten, vorwiegend acinuszentralen Ver~inderungen der Hepatocyten: Glykogenschwund, Disorganisation der Ergastoplasmaschollen, in manchen Zellen Verlust der cytoplasmatischen Basophilie oder Pyroninophilie, Nekrosen, Zunahme der Aktivit~it der sauren DNAse und RNAse. Nach Absetzen des Carcinogens erweisen sich diese Zellver~inderungen als reversibel. Sie werden daher auf die unspezifisch-toxische Wirkung des Carcinogens zuriickgeffihrt. In peripheren und intermedi~iren L~ippchenregionen kommt es zu grunds~itzlich anderen Zellver~inderungen. Sie sind w~ihrend der Vergiftungsphase unbedeutend, treten nach Absetzen des Carcinogens abet bei allen Tieren deutlich hervor: fiberm~il]ige Glykogenspeicherung, Dislokation der Ergastoplasmaschollen, Zunahme der cytoplasmatischen Acidophilie. Hepatocyten mit diesen Cytoplasmaalterationen bilden zun~ichst Herde. Sp~iter entwickeln sich neoplastische Knoten und ausgepr~igte hepatocellul~ire Carcinome. In den sp~iten Versuchsstadien bestehen sowohl die Herde als auch die neoplastischen Knoten im wesentlichen aus 4 verschiedenen cellul~iren Sch~idigungstypen: 1. ,,klare" Glykogenspeicherzellen, 2. acidophile Zellen, 3. vacuolisierte (fettspeichernde) Zellen, 4. glykogenarme oder-freie basophile (pyroninophile) Zellen. Gr6Bere Knoten und Carcinome enthalten vorwiegend basophile Zellen. Die Aktivit~it der Nucleasen, speziell der sauren DNAse, geht in anf~inglich nur kleinen peripheren und intermedi~ren L~ippchenbezirken zurfick. Die Herde mit ver~inderter Enzymaktivit~it bilden sich in der Regel sp~iter aus als die Glykogenspeicherherde. In neoplastischen Knoten und Carcinomen zeigen die meisten Zellen einen vollst~indigen Verlust der Enzymaktivit~it, in nekrotischen Tumorzellen tritt die Enzymaktivit~it aber wieder in Erscheinung. Die fortschreitenden Ver~inderungen der Aktivit~it der Nucleasen scheinen eng mit der ph~inotypischen Ausbildung der Malignit~it verkniipft zu sein. Sie k~Snnten eine grundlegende Umstellung des Zellstoffwechsels anzeigen, die sich in einem relativ sp~iten Stadium der neoplastischen Zelltransformation ereignet.
Environmental Health Perspectives, 1987
This paper is the second chronological supplement to the Carcinogenic Potency Database, published earlier in this journal (1,2,. We report here results of carcinogenesis bioassays published in the general literature . This supplement includes results of 525 long-term, chronic experiments of 199 test compounds, and reports the same information about each experiment in the same plot format as the earlier papers: e.g., the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications for a description of the numerical index of carcinogenic potency (TD50), a guide to the plot of the database, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The three plots of the database are to be used together, since results of experiments published in earlier plots are not repeated. Taken together, the three plots include results for more than 3500 experiments on 975 chemicals.
Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals
Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 1993
A comparison of target organs for mutagens and non-mutagens is presented for 351 rodent carcinogens in the Carcinogenic Potency Database (CPDB) with mutagenicity evaluations in Salmonella. Results are consistent with the hypotheses that in high-dose rodent tests mitogenesis is important in the carcinogenic response for mutagens and non-mutagens alike, and that mutagens have a multiplicative interaction for carcinogenicity because they can both damage DNA directly and cause cell division at high doses. These hypotheses would lead one to expect several results that are found in the analysis:
Carcinogen Induced Unscheduled DNA Synthesis in Mouse Hepatocytes
Toxicologic Pathology, 1984
Mouse primary liver cell cultures were examined for evidence of unscheduled DNA synthesis (UDS) following treatment with the carcinogens; dimethylnitrosamine (DMNA), diethylnitrosamine (DENA), 2-acetylaminofluorene (2-AAF), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), benzo(a)pyrene (BP), dimethylbenzanthracene (DMBA), l,l,-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), safrole, diethylstilbestrol (DES), aflatoxin Bl (AFBl), and dieldrin and the noncarcinogens; dimethylformamide (DMF), fluorene, and pyrene. Mouse hepatocyte cultures were simultaneously treated with three concentrations of each compound and 'H-thymidine. After 24 hrs, cells were fixed and processed for autoradiography. 'H-thymidine incorporation in both experimental and control cell nuclei, as evidenced by autoradiographic grains, was quantitated microscopically. DMNA, DENA, 2-AAF, MNNC, BP, AFB, and DMBA significantly increased UDS over untreated cells at all concentrations studied. DDT, DMF, fluorene, pyrene, safrole, DES, and dieldrin were negative for UDS in all concentrations examined. DMNA, 2-AAF and MNNG were also studied for UDS induction in 2 hr old, 1 day old and 4 day old cultures. A progressive decrease in UDS with increased time after plating was found in DMNA and 2-AAF treated cultures. After 4 days DMNA and 2-AAF induced UDS only at the highest concentrations examined (lo-' M and M respectively). MNNG induced UDS at all time periods and concentrations sampled. An attempt to enhance the sensitivity of the UDS assay by inducing the mixed function oxidative enzyme activity in the hepatocytes with phenobarbital administered in vivo resulted in no statistically significant increase in UDS with DMNA, 2-AAF, MNNG, DDT, and dieldrin when compared with cells from non-induced animals. ' To whom reprints should be addrcsscd at hiedical College of Ohio. Dcpartmcnt of I'athology. 3000 Arlington Avenue.