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Decreased Hepatic Phosphoenolpyruvate Carboxykinase Gene Expression after 2,3,7,8-Tetrachlorodibenzo-p-dioxin Treatment: Implications for the Acute Toxicity of Chlorinated Dibenzo-p-dioxins in the Rat

  • B. U. Stahl
  • D. G. Beer
  • L. W. D. Weber
  • M. Lebofsky
  • K. Rozman
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 15)

Summary

Decreased activity of the the rate limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been recently suggested to be the critical lesion in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We now show that other toxicologically relevant chlorinated dibenzo-P-dioxins (CDDs), with chlorine substituents in the crucial 2-,3-,7-, and 8-positions, exert the same effect on PEPCK activity. The doses required to cause this enzyme inhibition are within the acutely toxic range for each homologue, suggesting the same mechanism of action for these compounds. To further investigate the mechanism whereby dioxins decrease PEPCK activity, Northern analysis was performed using a cDNA probe complementary to a portion of the PEPCK mRNA. We could demonstrate that after TCDD treatment hepatic PEPCK mRNA was decreased by as much as 90% compared to pair-fed control animals (day 8 after dosing). This decrease in PEPCK mRNA was paralleled by a decrease of the amount of PEPCK protein and enzymatic activity. These results indicate that the physiological changes which occur in TCDD-treated animals (decreased feed consumption, low plasma insulin and elevated plasma corticosterone levels) which under normal conditions increase PEPCK gene expression and enzyme activity, are not effective in stimulating PEPCK synthesis in TCDD-treated animals.

Keywords

Phosphoenolpyruvate Carboxykinase TCDD Treatment PEPCK Activity PEPCK Gene PEPCK mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • B. U. Stahl
    • 1
    • 2
  • D. G. Beer
    • 1
  • L. W. D. Weber
    • 1
    • 2
  • M. Lebofsky
    • 1
  • K. Rozman
    • 1
    • 2
  1. 1.Dept. of Pharmacol., Tox. and Therap.University of Kansas Med. Ctr.Kansas CityUSA
  2. 2.GSF - Institut für ToxikologieSection of Environmental ToxicologyNeuherbergGermany

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