Colchicine antimitosis abolishes CCl4 autoprotection

Abstract

A subtoxic dose of CCl4 is known to destroy liver microsomal cytochrome P-450 and this is widely accepted as the mechanism of CCl4 autoprotection. Circumstantial evidence suggests that while cytochrome P-450 is significantly decreased, this mechanism alone cannot explain the phenomenon of autoprotection. Previous studies have established that hepatocellular regeneration is stimulated as early as 6 hr after the administration of a low dose of CCl4. If the early phase stimulation of hepatocellular regeneration by the protective dose is indeed the mechanism of autoprotection, then ablation of this early phase of tissue healing by colchicine should result in an abolishment of autoprotection. Present studies were conducted to test this conceptual premise. The protection afforded by a low dose of CCl4 (LCCl4, 100 microliter/kg, ip) on the toxic effects of a subsequently administered moderately toxic dose of CCl4 (HCCL4, 2.5 ml/kg, ip) was established in male Sprague-Dawley rats. The protective dose provided 100% protection, whereas only 62.5% survival was observed when the corn oil vehicle was administered instead of the protective dose of LCCl4. Colchicine administration (1 mg/kg, ip in saline) 2 hr prior to the injection of LCCl4 led to a complete loss of autoprotection resulting in 100% mortality in rats given the HCCl4. Earlier studies have established that colchicine selectively suppresses the early phase of hepatocellular regeneration at 6 hr without influencing the second phase at 36-48 hr. The consequence of colchicine antimitosis on the toxicological endpoints of liver injury was evaluated by serum enzyme elevations and by histopathological examination of the liver during a time course of 6, 24, 48, 72, and 96 hr after the administration of HCCl4. In the autoprotection regime, after only a transient and modest elevation of serum alanine and aspartate transaminases, complete recovery occurred by 96 hr. Hepatocellular necrosis was consistently lower compared to all other groups. Colchicine preadministration in the autoprotection regime resulted in significantly greater and progressive elevation of the serum enzymes and a correspondingly commensurate progression of hepatic lesion. Toxic effects of HCCl4 alone were more rapidly and maximally augmented by colchicine preadministration. The role of hepatocellular regeneration in autoprotection was evaluated by 3H-thymidine incorporation in hepatocellular nuclear DNA and by morphometric estimation of mitotic index. While HCCl4 alone resulted in some stimulation of 3H-thymidine incorporation and mitosis, the regenerative activity observed with prior LCCl4 administration was remarkably greater, particularly at 48 hr. Colchicine preadministration in either of these 2 protocols decisively obtunded the stimulated regenerative activities essentially abolishing the tissue healing mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)