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Archives of Toxicology

, Volume 63, Issue 5, pp 367–375 | Cite as

Role of hepatocellular regeneration in chlordecone potentiated hepatotoxicity of carbon tetrachloride

  • Prasada Rao S. Kodavanti
  • Urmila M. Joshi
  • Robert A. Young
  • Andrea N. Bell
  • Harihara M. Mehendale
Original Articles

Abstract

Previous histomorphometric studies led us to hypothesize that suppression of hepatocellular regeneration and the repair of the hepatolobular architecture was involved besides bioactivation phenomenon in the progressive and irreversible phase of toxicity resulting from CD + CCl4 interaction. We have recently observed significant protection from CD potentiated CCl4 toxicity in animals which are stimulated for active hepatocellular regeneration. The present work is an extension of our earlier histomorphometric investigation, taking 3H-thymidine (3H-T) incorporation as a biochemical parameter to assess hepatocellular regeneration followed by autoradiographic analysis of liver sections in normal (N) or chlordecone (CD) treated (10 ppm in diet for 15 days) male rats undergoing sham (SH) or partial hepatectomies (PH). Initial experiments established that in normal (N) rats, greatest 3H-T incorporation into hepatocellular nuclear DNA occurs at 2 days post-PH which returns to basal levels by 7 days. CD treatment alone did not change this phenomenon. 3H-T incorporation into nuclear DNA and the percentage of labelled cells as evidenced by autoradiography of liver sections were significantly elevated in N rats at 1–2 h after CCl4 (100 μl/kg) administration and returned to basal level by 6 h. Serum enzymes (AST and ALT) in N rats undergoing SH and PH were not altered, but were significantly elevated in CD rats following CCl4 (100 μl/kg) administration. CCl4-induced serum enzyme elevations were significantly lower in 2 days post-PH (PH2) rats when compared to SH rats or 7 days post-PH (PH7) rats maintained on CD diet, indicating that CD potentiated CCl4 hepatotoxicity is significantly reduced in livers stimulated for regenerative activity by PH. CCl4 decreased the DNA levels significantly in SH2, SH7 and PH7 rats, but not in PH2 rats receiving CD diet. 3H-T incorporation, percentage of labelled cells and number of grains per cell were significantly decreased at 2 h in PH2 rats receiving the CD + CCl4 combination treatment, reflecting the suppression of cell proliferation after CCl4 administration to CD fed rats. These results indicate that PH affords protection against CD + CCl4 interaction. The protection against hepatotoxic and lethal effects of CD + CCl4 combination by previously stimulated hepatocellular regeneration might be explained by two consequences of stimulated cell division. First, the hepatocellular architecture is renovated by the newly divided cells. Second, by virtue of the well known resistance of the newly divided cells, the progressive phase of toxicity is inhibited. These findings are supportive of our hypothesis that suppression of hepatocellular regeneration besides bioactivation phenomenon is involved in CD + CCl4 toxicity.

Key words

Chlordecone Carbon tetrachloride Partial hepatectomy 3H-thymidine incorporation DNA Potentiation Autoradiography 

Abbreviations

CD

chlordecone

PH

partial hepatectomy

SH

sham operation

PH2

2 days post-PH

SH2

2 days post-SH

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Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Prasada Rao S. Kodavanti
    • 1
  • Urmila M. Joshi
    • 1
  • Robert A. Young
    • 1
  • Andrea N. Bell
    • 1
  • Harihara M. Mehendale
    • 1
  1. 1.Department of Pharmacology and ToxicologyUniversity of Mississippi Medical CenterJacksonUSA

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