INCREASED POLYPLOIDY, DELAYED MITOSIS AND REDUCED PROTEIN PHOSPHATASE-1 ACTIVITY ASSOCIATED WITH EXCESS COPPER IN THE LONG-EVANS CINNAMON RAT

Citation
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
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Pharmacy",Pathology,Biology
ISSN journal
1078-0297
Volume
99
Issue
3
Year of publication
1998
Pages
283 - 304
Database
ISI
SICI code
1078-0297(1998)99:3<283:IPDMAR>2.0.ZU;2-C
Abstract
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.