EFFECT OF ANTIMITOTIC AGENT COLCHICINE ON CARBON-TETRACHLORIDE TOXICITY

A single administration of a subtoxic dose of CCl4 (100 mul/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 i njury associated with that dose of CCl4. Substantial evidence has accu mulated to indicate that the early-phase hepatocellular regeneration a nd tissue repair are critical for recovery from halomethane hepatotoxi city. The objective of these studies was to test this concept in an ex perimental framework, wherein a selective ablation of the early-phase cell division should result in prolongation of liver injury followed b y recovery. The studies were designed to evaluate the influence of the antimitotic agent colchicine (1 mg/kg, i.p. in saline) on CCl4 toxici ty. Colchicine was administered 2 h prior to CCl4 or com 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 inj ury was assessed through elevations of serum alanine and aspartate ami notransferase and by histopathological examination of the liver. Incor poration of H-3-thymidine in hepatocellular nuclear DNA and mitotic in dex were used as indices of hepatocellular regeneration. Hepatocellula r regeneration stimulated by CCl4 at 2-6 h was blocked by colchicine a s evidenced by the decreased H-3-thymidine incorporation and mitotic i ndex, without any significant effect on the second phase of cell divis ion at 48 h. Ablation of this early phase of tissue repair resulted in prolongation of CCl4 hepatotoxicity. Rats treated with CCl4 alone rec overed promptly within 24 h, whereas, colchicine pretreated rats recov ered from liver injury after 48 h. Morphometric analysis of hepatocell ular 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 inve stigated in vivo. (CCl4)-C-14-derived (CO2)-C-14 exhalation, covalent binding of (CCl4)-C-14 and (CCl4)-C-14-derived total radiolabel in the liver and lipid peroxidation were unaltered by colchicine pretreatmen t. These findings suggest the pivotal importance of the early- as well as the late-phase stimulation of hepatocellular regeneration and tiss ue healing processes in determining the final outcome of CCl4-induced liver injury.