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Onset of hepatocarcinogen‐specific cell proliferation and cell cycle aberration during the early stage of repeated hepatocarcinogen administration in rats
Author(s) -
Kimura Masayuki,
Abe Hajime,
Mizukami Sayaka,
Tanaka Takeshi,
Itahashi Megu,
Onda Nobuhiko,
Yoshida Toshinori,
Shibutani Makoto
Publication year - 2016
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.3163
Subject(s) - downregulation and upregulation , cell growth , cell cycle , cancer research , cell cycle checkpoint , biology , carcinogen , retinoblastoma protein , microbiology and biotechnology , chemistry , cell , biochemistry , gene
We have previously reported that a 28‐day treatment of carcinogens evoking target cell proliferation activates G 1 /S checkpoint function and apoptosis, as well as induction of aberrant ubiquitin D (Ubd) expression, suggesting disruptive spindle checkpoint function, in rats. The present study aimed to determine the onset time of rat liver cells to undergo carcinogen‐specific cell cycle aberration and proliferation. Animals were treated orally with a hepatocarcinogenic dose of methyleugenol or thioacetamide for 3, 7 or 28 days. For comparison, some animals were subjected to partial hepatectomy or treated with noncarcinogenic hepatotoxicants (acetaminophen, α‐naphthyl isothiocyanate or promethazine). Carcinogen‐specific liver cell kinetics appeared at day 28 as evident by increases of cell proliferation, p21 Cip1+ cells, phosphorylated‐Mdm2 + cells and cleaved caspase 3 + cells, and upregulation of DNA damage‐related genes. Hepatocarcinogens also downregulated Rbl2 and upregulated Cdkn1a and Mdm2 , and decreased Ubd + cells co‐expressing phosphorylated‐histone H3 (p‐Histone H3) and p‐Histone H3 + cell ratio within the Ki‐67 + proliferating population. These results suggest that it takes 28 days to induce hepatocarcinogen‐specific early withdrawal of proliferating cells from M phase due to disruptive spindle checkpoint function as evidenced by reduction of Ubd + cells staying at M phase. Disruption of G 1 /S checkpoint function reflected by downregulation of Rbl2 as well as upregulation of Mdm2 suggestive of sequestration of retinoblastoma protein is responsible for the facilitation of carcinogen‐induced cell proliferation at day 28. Accumulation of DNA damage probably in association with facilitation of p53 degradation by activation of Mdm2 may be a prerequisite for aberrant p21 Cip1 activation, which is responsible for apoptosis. Copyright © 2015 John Wiley & Sons, Ltd.