Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl Strasse 3/1, 6020 Innsbruck, Austria.
Arch Toxicol. 2013 Jan;87(1):49-72. doi: 10.1007/s00204-012-0919-y. Epub 2012 Aug 28.
The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.
人类基因组计划的完成以及随后 DNA 微阵列和高通量测序技术的出现，引发了分子毒理学的复兴。来自体内和体外研究的毒代基因组数据集呈指数级增长，为转录组水平上应激途径的调控提供了丰富的信息。通过这些研究，我们开始了解生物对外源化学物质的反应的多样性和复杂性。在这篇综述中，我们旨在整合和总结主要的与毒理学相关的转录因子调控的分子途径。很明显，不同的化学实体可以引起氧化应激、遗传毒性和蛋白毒性应激，从而诱导细胞产生反应以恢复内稳态。涉及的主要反应途径包括 NFE2L2（Nrf2）、NFE2L1（Nrf1）、p53、热休克因子和未折叠蛋白反应。此外，还存在一些更具体的机制，其中外源化学物质作为配体，包括芳香烃受体、金属反应转录因子 1 和核受体家族转录因子。其他途径，包括免疫调节转录因子 NF-κB 和 STAT 以及缺氧诱导转录因子 HIF，也与细胞对外源化学物质暴露的反应有关。转录活性控制的细胞损伤的一个不太具体但同样重要的方面是组织特异性基因表达的丧失，导致靶细胞去分化和组织功能受损。在这里，我们综述了这些途径及其调控的基因，以提供分子毒理学这一不断发展的领域的概述。
