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Effect of antimitotic agent colchicine on carbon tetrachloride toxicity

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Abstract

A single administration of a subtoxic dose of CCl4 (100 μl/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 of3H-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 decreased3H-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 hepatotoxicity. Rats treated with CCl4 alone recovered promptly within 24 h, whereas, colchicine pretreated rats recovered from liver injury after 48 h. Morphometric analysis of hepatocellular necrosis revealed that liver injury at 6 and 12 h after CCl4 was similar in rats regardless of colchicine pretreatment, indicating that prolongation of liver injury was due to delayed liver tissue healing mechanisms. The possibility that prolongation of hepatotoxicity is due to colchicine-induced enhancement of CCl4 metabolism was further investigated in vivo.14CCl4-derived14CO2 exhalation, covalent binding of14CCl4 and14CCl4-derived total radiolabel in the liver and lipid peroxidation were unaltered by colchicine pretreatment. These findings suggest the pivotal importance of the early- as well as the late-phase stimulation of hepatocellular regeneration and tissue healing processes in determining the final outcome of CCl4-induced liver injury.

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Abbreviations

ALT:

alanine transaminase

AST:

aspartate transaminase

CLC:

colchicine

CD:

chlordecone

3H-T:

3H-thymidine

PB:

phenobarbital

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Authors and Affiliations

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

    Vaman C. Rao & Harihara M. Mehendale

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  1. Vaman C. Rao
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  2. Harihara M. Mehendale
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Additional information

A preliminary report of these findings was presented at the ASPET 1990 meeting in Milwaukee, WI [Pharmacologist (1990) 32, 272].

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Rao, V.C., Mehendale, H.M. Effect of antimitotic agent colchicine on carbon tetrachloride toxicity. Arch Toxicol 67, 392–400 (1993). https://doi.org/10.1007/BF01977400

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  • DOI: https://doi.org/10.1007/BF01977400

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