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Toxicologic Pathology
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Journal Article

Pivotal Role of Hepatocellular Regeneration in the Ultimate Hepatotoxicity of CCl 4 in Chlordecone-, Mirex-, or Phenobarbital-Pretreated Rats

Prasada Rao S. Kodavanti

Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences Northeast Louisiana University, Monroe, Louisiana 71209-0470

Urmila P. Kodavanti

Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences Northeast Louisiana University, Monroe, Louisiana 71209-0470

Obaid M. Faroon

Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences Northeast Louisiana University, Monroe, Louisiana 71209-0470

Harihara M. Mehendale

Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences Northeast Louisiana University, Monroe, Louisiana 71209-0470

Our earlier histomorphometric and biochemical studies suggested that the progressive phase of the interactive toxicity of chlordecone (CD) + CCl4 involves suppression of hepatocellular regeneration. The objective of the present work was to correlate hepatocellular regeneration with CCl4 (100 µl/kg)-induced hepatotoxicity in rats maintained for 15 days on a normal (N) diet, relative to the regenerative response in rats maintained on a diet containing either 10 ppm CD, 225 ppm phenobarbital (PB), or 10 ppm mirex (M). Hepatocellular regeneration was assessed by measuring DNA and 3H-thymidine (3H-T) incorporation, followed by autoradiographic analysis of liver sections. Hepatotoxicity was assessed by measuring plasma transaminases (aspartate and alanine) followed by histopathological observations of liver sections for necrotic, swollen, and lipid-laden cells. Lethality studies were also carried out to assess the consequence of hepatotoxicity on animal survival. Dietary 10 ppm CD potentiated the hepatotoxicity of CCl4 to a greater extent than PB or M, as evidenced by elevations in plasma enzymes. Although the serum enzymes were significantly elevated in PB rats in contrast to the slight elevations in N and M rats, they returned to normal levels by 96 hr. However, serum enzyme elevations in CD rats were progressive with time until death of the animals. Actual liver injury by CCl4 was greater in PB- than in CD-pretreated rats, as evidenced by histopathological observations. A 100% mortality occurred in CD-pretreated rats at 60 hr after CCl4 administration, whereas no mortality occurred in either N-, M-, or PB-pretreated rats, indicating recovery from liver injury. Hepatocellular nuclear DNA levels were significantly decreased starting at 6 hr after CCl4 administration to CD-pretreated rats, but not in M- or PB-pretreated rats. 3H-T incorporation into nuclear DNA as well as percentage of labeled cells showed a biphasic increase in N rats: 1 at 1-2 hr, and the other at 36-48 hr after CCl 4 administration. However, only 1 peak of 3H-T incorporation at 36-48 hr was observed in the CD + CCl4 combination, which was also significantly lower when compared to that observed after the M or PB + CCl4 combination treatments. These findings suggest that there is recovery in N-, PB-, or M-pretreated rats from CCl4-induced injury by virtue of the stimulated hepatocellular regeneration and tissue repair. In CD-pretreated rats, CCl4 toxicity is progressive because of mitigated hepatocellular regeneration (at 2-6 hr), supporting the concept that hepatocellular regeneration plays a critical role in determining whether hepatotoxicity becomes permissively progressive or actively regressive, owing to tissue repair mechanisms. In the absence of hepatocellular regeneration and tissue repair, progressive liver injury leads to sustained hepatic failure (24 hr), culminating in animal death. These findings underscore the importance of assessing additional parameters of hepatobiology indicative of the ultimate outcome of toxicity rather than relying solely on indices of liver injury, particularly during the inflictive phase of chemically-induced liver injury.

Key Words: Mirex • carbon tetrachloride • potentiation

Toxicologic Pathology, Vol. 20, No. 4, 556-569 (1992)
DOI: 10.1177/019262339202000402
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[Abstract] [PDF]

This Article
Right arrow Abstract Freely available
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Citing Articles
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Right arrow Articles by Kodavanti, P. R. S.
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PubMed
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Right arrow Articles by Kodavanti, P. R. S.
Right arrow Articles by Mehendale, H. M.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CARBON TETRACHLORIDE
*CHLORDECONE
*MIREX
*PHENOBARBITAL
*TRITIUM
Medline Plus Health Information
*Liver Diseases
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
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