Gene expression profiling of rat livers reveals indicators of potential adverse effects
Gene expression profiling of rat livers reveals indicators of potential adverse effects
复制标题
DOI：
10.1093/toxsci/kfh145
复制
发表时间：
2004-07-01
影响因子：
3.8
通讯作者：
Paules, RS
中科院分区：
文献类型：
--
作者：
Heinloth, AN;Irwin, RD;Paules, RS
本研究测试了基因表达谱可以揭示由低剂量物质诱导的对肝脏的细微损伤的指标的假设，所述低剂量物质不会引起如由常规毒理学标准定义的明显毒性（例如，异常临床化学和组织病理学）。出于本研究的目的，我们将该低剂量定义为亚毒性，即，所述剂量引起的效应低于常规毒理学参数的检测。选择对乙酰氨基酚（APAP）作为肝毒性模型，因为（1）存在大量关于高剂量后可能发生的APAP肝毒性机制的信息，（2）APAP中毒是美国急诊室就诊涉及急性肝衰竭的主要原因，（3）常规临床标志物的预测价值较差。在暴露后6、24或48 h，对单剂量0、50、150或1500 mg/kg APAP处理的大鼠进行常规毒理学参数和基因表达改变检查。基因表达模式的发现表明细胞能量损失的后果APAP毒性。这些模式的要素是明显的，即使在暴露于亚毒性剂量。随着剂量的增加，变化幅度增加，相同生物学途径的其他成员差异表达。在1500 mg/kg剂量暴露下，通过测量ATP水平证实了基因表达变化所提示的能量损失。只有通过超微结构检查，才能发现暴露于亚毒性剂量的APAP后的任何毒性迹象，即偶尔的线粒体损伤。总之，本研究提供的证据支持以下假设，即基因表达谱分析可能是在不发生明显毒性的情况下识别潜在不良反应指标的敏感方法。
This study tested the hypothesis that gene expression profiling can reveal indicators of subtle injury to the liver induced by a low dose of a substance that does not cause overt toxicity as defined by conventional criteria of toxicology (e.g., abnormal clinical chemistry and histopathology). For the purpose of this study we defined this low dose as subtoxic, i.e., a dose that elicits effects which are below the detection of conventional toxicological parameters. Acetaminophen (APAP) was selected as a model hepatotoxicant because (1) considerable information exists concerning the mechanism of APAP hepatotoxicity that can occur following high doses, (2) intoxication with APAP is the leading cause of emergency room visits involving acute liver failure within the United States, and (3) conventional clinical markers have poor predictive value. Rats treated with a single dose of 0, 50, 150, or 1500 mg/kg APAP were examined at 6, 24, or 48 h after exposure for conventional toxicological parameters and for gene expression alterations. Patterns of gene expression were found which indicated cellular energy loss as a consequence of APAP toxicity. Elements of these patterns were apparent even after exposure to subtoxic doses. With increasing dose, the magnitude of changes increased and additional members of the same biological pathways were differentially expressed. The energy loss suggested by gene expression changes was confirmed at the 1500 mg/kg dose exposure by measuring ATP levels. Only by ultrastructural examination could any indication of toxicity be identified after exposure to a subtoxic dose of APAP and that was occasional mitochondrial damage. In conclusion, this study provides evidence that supports the hypothesis that gene expression profiling may be a sensitive means of identifying indicators of potential adverse effects in the absence of the occurrence of overt toxicity.