Value of monitoring Nrf2 activity for the detection of chemical and oxidative stress.
Value of monitoring Nrf2 activity for the detection of chemical and oxidative stress.
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DOI：
10.1042/bst20150044
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发表时间：
2015-08
影响因子：
3.9
通讯作者：
Copple IM
中科院分区：
文献类型：
--
作者：
Mutter FE;Park BK;Copple IM
超出特定的暴露限度，化学实体可能通过与关键大分子的直接相互作用或刺激活性氧（ROS）的积累而对哺乳动物细胞产生有害影响。特别是，这些化学和氧化应激可能会加剧治疗药物的不良反应，这给临床和制药行业带来不必要的负担。需要新的临床前测试策略来在开发途径的早期阶段识别可能引起人类毒性的化学品和药物。哺乳动物细胞可以通过转录因子核因子红细胞 2 相关因子 2 (Nrf2) 的作用来适应化学和氧化应激，该因子上调多种细胞防御基因的表达，并已被证明可以防止多种化学毒性。在这里，我们对 Nrf2 通路进行了简要概述，并总结了可用于监测 Nrf2 通路活性变化的新实验模型，从而了解此类扰动在化学和药物毒性背景下的功能后果。我们还对监测 Nrf2 活性的潜在价值进行了展望，以改善对人类具有毒性作用的化学品和药物的临床前鉴定。
Beyond specific limits of exposure, chemical entities can provoke deleterious effects in mammalian cells via direct interaction with critical macromolecules or by stimulating the accumulation of reactive oxygen species (ROS). In particular, these chemical and oxidative stresses can underpin adverse reactions to therapeutic drugs, which pose an unnecessary burden in the clinic and pharmaceutical industry. Novel pre-clinical testing strategies are required to identify, at an earlier stage in the development pathway, chemicals and drugs that are likely to provoke toxicity in humans. Mammalian cells can adapt to chemical and oxidative stress via the action of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which up-regulates the expression of numerous cell defence genes and has been shown to protect against a variety of chemical toxicities. Here, we provide a brief overview of the Nrf2 pathway and summarize novel experimental models that can be used to monitor changes in Nrf2 pathway activity and thus understand the functional consequences of such perturbations in the context of chemical and drug toxicity. We also provide an outlook on the potential value of monitoring Nrf2 activity for improving the pre-clinical identification of chemicals and drugs with toxic liability in humans.