title: [Different sensitivity of inbred mice to hepatocarcinogen ortho-aminoazotoluene may be due to differences in the negative control mechanisms of hepatocyte proliferation].
abstract: A most convenient model to study mechanisms of live organism response to chemical carcinogens is tumor induction in murine liver by aminoazodyes, in particular by ortho-aminoazotoluene (OAT). We studied both early and late stages of hepatocarcinogenesis on several lines of inbred mice differing in sensibility to OAT. By means of autoradiography, we examined proliferative activity of hepatocytes obtained from the liver of sensitive (A/He, DD, SWR) and resistant to OAT AKR, CC57Br, BALB/c lines of mice, which were injected carcinogen. The level of p53, p21Cip1, bax, mdm2, cyclin G, gadd45 genes expression in the liver of mice of different lines given OAT injection was studied by multiplex PCR method. Carcinogen caused a decrease of hepatocyte proliferative activity induced by partial hypatectomy (PHE), and an increase in p53, p21Cip, bax, mdm2, and cyclin G genes within mice of A/He, DD and SWR lines. Cell fusion experiments on hepatocytes obtained from regenerating murine liver sensitive to A/He line carcinogen and given long-time OAT administrations with resting and proliferating fibroblasts of NIH 3T3 mice revealed no obvious suppression of DNA synthesis in heterokaryons. Unlike, in fusion experiments on serum-stimulated fibroblasts with hepatocytes obtained from the liver of BALB/c line mice also given OAT suppression of DNA synthesis in stimulated fibroblasts in heterokaryons was observed 15 days following PHE. These results enable us to conclude that OAT administrations break negative endogenous mechanisms of hepatocyte proliferation control in the liver of mice sensitive to carcinogenes.
authors.forename: A V
authors.initials: AV
authors.lastname: Eremeev
authors.forename: O A
authors.initials: OA
authors.lastname: Timofeeva
authors.forename: V I
authors.initials: VI
authors.lastname: Kaledin
authors.forename: N A
authors.initials: NA
authors.lastname: Setkov
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002459:Cell Fusion; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D009762:o-Aminoazotoluene / Q000633:toxicity*
chemical_list: C494827:Bax protein, mouse; D002273:Carcinogens; C534703:Ccng1 protein, mouse; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D009762:o-Aminoazotoluene