Increased polyploidy, delayed mitosis and reduced protein phosphatase-1 activity associated with excess copper in the long evans cinnamon rat

Takahisa Yamada, Kenichi Sogawa, Jin Kyung Kim, Keisuke Izumi, Yasuo Suzuki, Youji Muramatsu, Tomoki Sumida, Hiroyuki Hamakawa, Kozo Matsumoto

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Abstract

Until now, it is not known whether copper hepatotoxicity impairs mitosis. Enlarged hepatocytes with huge nuclei considered as polyploids are frequently observed in the Long Evans Cinnamon (LEC) rat which exhibits an abnormal accumulation of hepatic copper due to a defect in the gene homologous to human Wilson's disease gene responsible for intracellular copper delivery. This defect may lead to a abnormal mitotic progression in increased polyploidization and is associated with excessive hepatic copper. This study was designed to examine whether excess copper impairs mitotic progression and results in increased polyploidization using a model of LEC rat liver. Polyploidy was analyzed by flow cytometry. The rate of mitotic progression was investigated using the fraction of mitotic hepatocytes or a mitosis-specific phosphoprotein retained in regeneration. Nuclear protein phosphatase-1 (PP-1) activity essential to mitotic progression was measured. The effect of excess copper on incidence of polyploidy, the rate of mitotic progression and nuclear PP-1 activity was investigated using age- or copper overload-dependent changes in them in LEC rat, or genetic profile-dependent changes of them in backcrosses. LEC rat liver showed an increase of polyploidy, a delay of mitotic progression, and a reduction of nuclear PP-1 activity. These abnormal features concurred with increase of copper concentration accompanied by changes of age in LEC rats from 2 to 4 months of age, induced by dietary copper overload in LEC rat, or caused by single genetic defect in backcrosses. Excess copper impairs mitotic progression, resulting in increased polyploidization. Nuclear PP- 1 activity is likely to be at least one of targets of copper hepatotoxicity leading to impairment of mitotic progression.

Original languageEnglish
Pages (from-to)283-304
Number of pages22
JournalResearch Communications in Molecular Pathology and Pharmacology
Volume99
Issue number3
Publication statusPublished - Mar 1 1998
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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