Increased polyploidy, delayed mitosis and reduced protein phosphatase-1 activity associated with excess copper in the Long Evans Cinnamon rat.
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.
Yamada
T
T
Institute for Animal Experimentation, University of Tokushima School of Medicine, Japan.
Sogawa
K
K
Kim
J K
JK
Izumi
K
K
Suzuki
Y
Y
Muramatsu
Y
Y
Sumida
T
T
Hamakawa
H
H
Matsumoto
K
K
D000367:Age Factors; D000824:Animal Nutritional Physiological Phenomena; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology; D003300:Copper / Q000097:blood / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008938:Mitosis / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011123:Polyploidy; D054645:Protein Phosphatase 1; D051381:Rats; D011916:Rats, Inbred F344
D003300:Copper; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1