DIFFERENT SENSIBILITY OF INBRED MICE TO HEPATOCARCINOGEN ORTHO-AMINOAZOTOLUEN MAY BE DUE
TO DIFFERENCES IN THE NEGATIVE CONTROL MECHANISMS OF HEPATOCYTE PROLIFERATION
A. V. Eremeev, 1 0. A. Timofeeva, 2 V. I. Kaledin, 3
N. A. Setkov 1
1 Institute of Biophysics, Siberian Branch of RAS, Krasnoyarsk, 2
Institute of Bioorganic Chemistry, Siberian Branch of RAS, and 3 Institute of Cytology and Genetics, Siberian Branch of RAS,
Novosibirsk, Russia;
e-mail: libibp@ibp.ru
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 ð53, ð21Cip1, mdm2, bax, 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 mp53, ð21Cip1, 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.
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