Effect of colchicine on hepatobiliary function in CCl4 treated rats.

Abstract A number of toxic chemicals affect the biliary excretory function of liver. Organochlorines and halomethanes are known to enhance bile flow. Despite the demonstration that a diversity of agents modify biliary function, the mechanism by which these chemicals manifest this effect is not fully understood. This study was designed to assess the effect of colchicine (0.1, 1.0, or 2.5 mg/kg, i.p., in saline) administration on biliary excretory function 6 and 24 hr later. Additionally, the effect of colchicine (1 mg/kg, i.p. in saline) pretreatment in rats 2 hr prior to the administration of a single low dose of CCl 4 (100 μL/kg, i.p., in corn oil) or corn oil alone (1 mL/kg, i.p.) on hepatic biliary excretory function was also assessed at 6 and 24 hr after the last treatment. The hepatotoxicity was evaluated by serum enzymes, alanine and aspartate aminotransferases, and histopathological alterations of the liver. Biliary excretion of intravenously administered phenolphthalein glucuronide (PG) was assessed in bile duct cannulated anesthetized rats. Only the highest dose of colchicine (2.5 mg/kg) resulted in detectable liver injury as revealed by elevations of serum transaminases. While the lowest dose of colchicine (0.1 mg/kg) did not influence bile secretion, the two higher doses caused a slight choleretic effect at 24 hr. The highest dose caused a transient inhibition of bile flow, but this effect was no longer evident at 6hr. Biliary excretion of PG was inhibited significantly by colchicine within 6 hr after administration, an effect that was also persistent at 24 hr. Colchicine at a 1 mg/kg dose did not cause any adverse effect on hepatobiliary function. Therefore, for the interactive toxicity study with CCl 4 , 1 mg colchicine/kg was chosen as a moderate dose which did not cause any significant adverse effect on hepatobiliary function. Biliary excretion of PG was significantly lower in rats at 6 and 24 hr after the combination treatment with colchicine + CCl 4 than in rats receiving either CCl 4 or colchicine alone. In contrast, rats receiving CCl 4 alone or colchicine + CCl 4 showed a significant increase in cumulative bile flow at 6 hr, whereas, at 24 hr, the bile flow was increased significantly in rats receiving colchicine regardless of CCl 4 treatment. The data suggest that colchicine pretreatment leads to significant inhibition of hepatobiliary excretion in CCl 4 treated rats. Serum alanine transaminase and aspartate transaminase levels were elevated significantly after the colchicine + CCl 4 combination, indicating hepatic injury. Histological examination of the liver revealed that although CCl 4 alone caused observable liver injury at 6 hr, these rats recovered from liver injury at 24 hr. In contrast, a marked increase was evident in the number of necrotic and swollen hepatocytes in colchicine + CCl 4 treated rats, which persisted even at 24 hr after CCl 4 treatment. In conclusion, a single administration of colchicine at 0.1 or 1 mg/kg did not cause any hepatic toxicity and did not affect hepatobiliary function significantly. At 2.5 mg/kg, colchicine caused detectable liver injury and adversely affected hepatobiliary function. The combination of colchicine (1 mg/kg) and CCl 4 (100 μL/kg) at individually nontoxic doses resulted in prolongation of CCl 4 toxicity.