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

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• 作者：Sreedevi Avasarala ; Lei Yang ; Yan Sun ; Alice Wan-Chi Leung ; Wood-Yee Chan ; Wing-Tai Cheung ; Susanna Sau-Tuen Lee
• 关键词：Carbon tetrachloride ; Cyp2e1-null mice ; Fluorescent differential display ; Gene expression profiling ; Oxidative stress
• 刊名：Toxicology
• 出版年：2006
• 出版时间：7 December 2006
• 年：2006
• 卷：228
• 期：2-3
• 页码：310-322
• 全文大小：1654 K

文摘

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 Cyp2e1^−/− 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 Cyp2e1^−/− 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 Cyp2e1^−/− 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.