Jiang Youchun, Liu Jie, Waalkes Michael, Kang Y James
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.
Toxicol Sci. 2004 Jun;79(2):404-10. doi: 10.1093/toxsci/kfh120. Epub 2004 Mar 31.
Recent studies have shown that gene expression profiles change in the livers of animals treated acutely with toxic chemicals such as carbon tetrachloride (CCl(4)). This study was undertaken to evaluate the changes in gene expression in mouse liver immediately after a long-term treatment with CCl(4) and possible effects of treatment cessation on these changes. Adult 129/Sv(pc)J mice were treated twice a week with CCl(4) at 1 ml/kg in olive oil for 4 weeks. Hepatic pathological changes observed in the CCl(4)-treated mice included necrosis, inflammation, and fibrosis, along with increased serum alanine aminotransferase activities. Consistent with these changes, expression of genes involved in cell death, cell proliferation, metabolism, DNA damage, and fibrogenesis were upregulated as detected by microarray analysis and confirmed by real-time RT-PCR. Four weeks after CCl(4) treatment cessation, the pathological changes were recovered, with the exception of fibrosis, which was not completely reversed. Most of the gene expression profiles also returned to the control level; however, the fibrogenetic genes remained at a high level of expression. These results demonstrate that changes in gene expression profile correlate with pathological alterations in the liver in response to CCl(4) intoxication. Most of these changes are recoverable upon withdrawal of the toxic insult. However, liver fibrosis is a prolonged change both in gene expression and histopathological alterations.
近期研究表明，用四氯化碳（CCl₄）等有毒化学物质急性处理动物后，其肝脏中的基因表达谱会发生变化。本研究旨在评估长期用CCl₄处理小鼠后肝脏中基因表达的变化，以及停止处理对这些变化可能产生的影响。成年129/Sv(pc)J小鼠每周两次用含1 ml/kg CCl₄的橄榄油进行处理，持续4周。在CCl₄处理的小鼠中观察到的肝脏病理变化包括坏死、炎症和纤维化，同时血清丙氨酸转氨酶活性增加。与这些变化一致，通过微阵列分析检测并经实时RT-PCR证实，参与细胞死亡、细胞增殖、代谢、DNA损伤和纤维生成的基因表达上调。停止CCl₄处理4周后，除纤维化未完全逆转外，病理变化得以恢复。大多数基因表达谱也恢复到对照水平；然而，纤维生成基因仍处于高表达水平。这些结果表明，基因表达谱的变化与肝脏对CCl₄中毒的病理改变相关。在撤去有毒刺激后，这些变化大多是可恢复的。然而，肝纤维化在基因表达和组织病理学改变方面都是一个长期的变化。
