T. Yamada et al., INCREASED POLYPLOIDY, DELAYED MITOSIS AND REDUCED PROTEIN PHOSPHATASE-1 ACTIVITY ASSOCIATED WITH EXCESS COPPER IN THE LONG-EVANS CINNAMON RAT, Research communications in molecular pathology and pharmacology, 99(3), 1998, pp. 283-304
Until now, it is not known whether copper hepatotoxicity impairs mitos
is. Enlarged hepatocytes with huge nuclei considered as polyploids are
frequently observed in the Long Evans Cinnamon (LEC) rat which exhibi
ts an abnormal accumulation of hepatic copper due to a defect in the g
ene homologous to human Wilson's disease gene responsible for intracel
lular copper delivery. This defect may lead to a abnormal mitotic prog
ression in increased polyploidization and is associated with excessive
hepatic copper. This study was designed to examine whether excess cop
per impairs mitotic progression and results in increased polyploidizat
ion using a model of LEC rat liver. Polyploidy was analyzed by flow cy
tometry. The rate of mitotic progression was investigated using the fr
action of mitotic hepatocytes or a mitosis-specific phosphoprotein ret
ained in regeneration. Nuclear protein phosphatase-1 (PP-1) activity e
ssential to mitotic progression was measured. The effect of excess cop
per on incidence of polyploidy, the rate of mitotic progression and nu
clear PP-1 activity was investigated using age-or copper overload-depe
ndent changes in them in LEC rat, or genetic profile-dependent changes
of them in backcrosses. LEC rat liver showed an increase of polyploid
y, a delay of mitotic progression, and a reduction of nuclear PP-1 act
ivity. These abnormal features concurred with increase of copper conce
ntration 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 si
ngle genetic defect in backcrosses. Excess copper impairs mitotic prog
ression, resulting in increased polyploidization. Nuclear PP-1 activit
y is likely to be at least one of targets of copper hepatotoxicity lea
ding to impairment of mitotic progression.