A temporal study on the histopathological, biochemical and molecular responses of CCl4-induced hepatotoxicity in Cyp2e1-null mice

Previous study using Cyp2e1-null mice showed that Cyp2e1 is required in CCl4-induced liver injury at 24 h, what remains unclear are the temporal changes in liver damage and the spectrum of genes involved in this process. We investigated the time-dependent liver changes that occurred at morphological, histopathological, biochemical and molecular levels in both Cyp2e1(+/+) and Cyp2el(-/-) mice after treating with either corn oil or CCl4 (1 ml/kg) for 2, 6, 12, 24 and 48 h. A pale orange colored liver, indicative of fatty infiltration, was observed in Cyp2e1(+/+) mice treated with CCl4 for 24 and 48 h, while the Cyp2e1(+/+) mice treated with corn oil and Cyp2el(-/-) mice treated with either corn oil or CCl4 showed normal reddish brown colored liver. Ballooned hepatocytes with multiple vacuoles in their cytoplasm were observed in the livers of Cyp2e1(+/+) mice 24 and 48 h after treating with CCl4. The levels of serum alanine aminotransferase and aspartate aminotransferase, markers for liver injury, were significantly higher at 12 h, peaked at 24 h and gradually decreased at 48 h after CCl4 intoxication. In contrast, this kind of damage was not apparent in the Cyp2el(-/-) mice treated with CCl4. Altered expressions of genes related to liver cirrhosis, apoptosis, oxidative stress, xenobiotic detoxification, lipid metabolism, chemsensory signaling or tumorigenesis, structural organization, regeneration and inflammatory response were identified, and the time-dependent changes in expression of these genes were varied. Overall, the present study provides insights into the mechanism of CCl4-induced hepatotoxicity in animal models. (c) 2006 Elsevier Ireland Ltd. All rights reserved.