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Decrease in protein kinase and phosphatase activities in the liver nuclei of rats exposed to carbon tetrachloride
M Omura1, T Katsumata, H Misawa
1Graduate School of Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka City, 422-8526, Japan.
Toxicology and Applied Pharmacology
|October 21, 1999
Summary
Carbon tetrachloride (CCl(4)) administration significantly reduces liver nuclear protein kinase and tyrosine phosphatase activities in rats. These changes impact key signaling pathways within liver cells.
Area of Science:
- Biochemistry
- Toxicology
- Molecular Biology
Background:
- Carbon tetrachloride (CCl(4)) is a known hepatotoxin.
- Protein kinases and phosphatases are crucial regulators of cellular signaling.
- Liver nuclei are key sites for gene regulation and metabolic control.
Purpose of the Study:
- To investigate the effects of CCl(4) on protein kinase and phosphatase activities in rat liver nuclei.
- To identify specific types of protein phosphatases affected by CCl(4) exposure.
- To explore the role of Ca(2+)/calmodulin and regucalcin in CCl(4)-induced alterations.
Main Methods:
- Rats were administered varying doses of CCl(4) orally.
- Liver nuclei were isolated at 5, 24, and 48 hours post-administration.
- Protein kinase and phosphatase activities (tyrosine, serine, threonine) were measured in vitro.
- Effects of activators (Ca(2+), calmodulin) and inhibitors (vanadate, okadaic acid, sodium fluoride, anti-regucalcin antibody) were assessed.
Main Results:
- CCl(4) administration significantly decreased nuclear protein kinase activity at 10% and 25% doses.
- Ca(2+)/calmodulin-dependent protein kinase activation was not suppressed by CCl(4).
- Nuclear phosphotyrosine phosphatase activity, but not phosphoserine/threonine phosphatase activity, was markedly decreased by CCl(4) (5-25%).
- This decrease in tyrosine phosphatase activity was evident as early as 5 hours after CCl(4) administration.
- Vanadate significantly inhibited phosphotyrosine phosphatase activity, while okadaic acid and sodium fluoride did not.
- Anti-regucalcin antibody increased phosphotyrosine phosphatase activity in CCl(4)-treated rats, suggesting reduced regucalcin-sensitive phosphatase activity.
Conclusions:
- CCl(4) administration induces a significant decrease in rat liver nuclear protein kinase activity.
- CCl(4) specifically reduces nuclear phosphotyrosine phosphatase activity, indicating a disruption in tyrosine phosphorylation signaling.
- Regucalcin-sensitive phosphatases are implicated in the CCl(4)-induced decrease in tyrosine phosphatase activity.
- These alterations in kinase and phosphatase activities likely contribute to the overall toxic effects of CCl(4) on the liver.