Effect of antimitotic agent colchicine on carbon tetrachloride toxicity.
A single administration of a subtoxic dose of CCl4 (100 microliters/kg, i.p.) is known to induce hepatocellular regeneration and tissue repair at 6 and 48 h in rats, permitting prompt recovery from the limited liver injury associated with that dose of CCl4. Substantial evidence has accumulated to indicate that the early-phase hepatocellular regeneration and tissue repair are critical for recovery from halomethane hepatotoxicity. The objective of these studies was to test this concept in an experimental framework, wherein a selective ablation of the early-phase cell division should result in prolongation of liver injury followed by recovery. The studies were designed to evaluate the influence of the antimitotic agent colchicine (1 mg/kg, i.p. in saline) on CCl4 toxicity. Colchicine was administered 2 h prior to CCl4 or corn oil injection. Toxicological end points and markers of hepatocellular regeneration were assessed at various time points (2, 6, 12, 24, 48 and 72 h) after the injection of CCl4 to male Sprague-Dawley rats. Hepatocellular injury was assessed through elevations of serum alanine and aspartate aminotransferase and by histopathological examination of the liver. Incorporation of 3H-thymidine in hepatocellular nuclear DNA and mitotic index were used as indices of hepatocellular regeneration. Hepatocellular regeneration stimulated by CCl4 at 2-6 h was blocked by colchicine as evidenced by the decreased 3H-thymidine incorporation and mitotic index,without any significant effect on the second phase of cell division at 48 h. Ablation of this early phase of tissue repair resulted in prolongation of CCl4 hepatoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)
Rao
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VC
Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470.
Mehendale
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HM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D002251:Carbon Tetrachloride / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D002452:Cell Count / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D003078:Colchicine / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008940:Mitotic Index / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D014316:Tritium; D002245:Carbon Dioxide; D004247:DNA; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003078:Colchicine; D013936:Thymidine