Department of Toxicogenetics, Leiden University Medical Center, PO Box 9600, 2300, RC, Leiden, The Netherlands.
J Appl Toxicol. 2013 Jun;33(6):399-409. doi: 10.1002/jat.2845. Epub 2013 Jan 22.
Most of the current in vitro carcinogenicity assays assess the potential carcinogenic properties of chemicals through the detection of inflicted DNA damage or subsequent chromosome damage and gene mutations. Unfortunately, these assays generally do not provide mechanistic insight into the reactive properties of a chemical. Upon chemical-induced damage of biomolecules, molecular sensors will activate general and damage-specific cellular response pathways that provide protection against the (geno)toxic and potential carcinogenic properties of chemicals. These cellular defense mechanisms include activation of cell-cycle checkpoints, DNA repair systems and induction of apoptosis or necrosis. Visualization of activated cellular-signaling pathways forms a powerful means to readily detect the genotoxic potential of chemical compounds and simultaneously gain insight into their reactive properties. Over the past years, various in vitro reporter assays have been developed that monitor activation of general and more specific cellular-signaling pathways, including the GreenScreen HC and ToxTracker assays. In this review we provide a perspective on how we can exploit activation of cellular signaling pathways to shed light on the mode of action of the chemical exposure and to develop sophisticated mechanism-based in vitro assays for cancer risk assessment.
目前大多数体外致癌性检测方法是通过检测化学物质引起的 DNA 损伤或随后的染色体损伤和基因突变，来评估化学物质的潜在致癌特性。不幸的是，这些检测方法通常不能提供对化学物质反应特性的机制见解。在生物分子受到化学物质诱导的损伤后，分子传感器将激活通用和损伤特异性的细胞反应途径，为化学物质的（遗传毒性和潜在致癌性）提供保护。这些细胞防御机制包括激活细胞周期检查点、DNA 修复系统以及诱导细胞凋亡或坏死。激活细胞信号通路的可视化是一种快速检测化学化合物遗传毒性潜力的有效手段，同时还可以深入了解其反应特性。在过去的几年中，已经开发出了各种体外报告基因检测方法，用于监测通用和更具体的细胞信号通路的激活，包括 GreenScreen HC 和 ToxTracker 检测方法。在这篇综述中，我们提供了一个视角，探讨如何利用细胞信号通路的激活来阐明化学暴露的作用模式，并开发用于癌症风险评估的复杂基于机制的体外检测方法。
