Abstract
Despite being a cardinal experimental model, the induction of cirrhosis in rats by repeated exposure to carbon tetrachloride (CCl4) has low reproducibility. Here, we compared two models of cirrhosis induced by orogastric administration of CCl4 once (CCl4-1xWk) or twice a week (CCl4-2xWk) for 12 weeks in male Sprague-Dawley rats. Control rats received water instead of CCl4. Both CCl4 protocols similarly attenuated body weight gain (p < 0.01 vs. Control). Although both CCl4 protocols increased hepatic fibrosis, portal hypertension and splenomegaly, the magnitude of these alterations was higher and more consistent in CCl4-2xWk rats. Importantly, two CCl4-1xWk rats did not develop cirrhosis versus a 100% yield of cirrhosis in CCl4-2xWk rats. The CCl4-2xWk protocol consistently induced liver atrophy together with hematological, biochemical and coagulation abnormalities characteristic of advanced cirrhosis that were absent in CCl4-1xWk rats. Ascites occurred in 20% and 80% of rats in theCCl4-1xWk and CCl4-2xWk groups (p < 0.01). All rats showed normal renal function, arterial blood gases and stable systemic hemodynamics. The total dose of CCl4 and mortality rate were similar in both protocols. The CCl4-2xWk protocol, therefore, was highly reproducible and effective for the induction of experimental cirrhosis within a confined time, representing a valuable advance for liver research.
Highlights
Acute CCl4 administration causes consistent hepatotoxicity due to reactive metabolites generated by cytochrome P-450 enzymes, primarily CYP2E1, expressed in perivenular hepatocytes
The impairment of body weight gain was similar in both CCl4 protocols, the rats receiving CCl4 once a week presented a highly serrated curve of body weight gain that contrasted with the smooth curve observed in the rats of the CCl4 2xWk group (Fig. 1 inset)
The experimental model of CCl4-induced cirrhosis has provided relevant insight into mechanisms of liver disease because CCl4-treated rats behave very different than normal rats despite the presence of widely heterogenous degrees of liver fibrosis in the former
Summary
Acute CCl4 administration causes consistent hepatotoxicity due to reactive metabolites generated by cytochrome P-450 enzymes, primarily CYP2E1, expressed in perivenular hepatocytes. Major problems of the experimental models of CCl4-induced cirrhosis are the unpredictable acute damage caused by CCl4 in each rat ( in initial doses), and the highly variable yield of cirrhosis. High yields of cirrhosis (100%) and ascites (>90%) have been reported using this protocol, the associated mortality is consistently high (40–60%) and the duration of CCl4 administration required to develop ascites is extremely variable (6 to 20 weeks) from one rat to another even within single studies. In 2008, Regimbeau et al reported a “rapid” protocol for the induction of cirrhosis involving the administration of CCl4 by oral gavage twice a week, with the CCl4 dose being adjusted to the body weight on the same day of treatment. The CCl4-2xWk protocol showed major improvements in terms of reproducibility and yield of cirrhosis, portal hypertension and ascites without increasing mortality
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