Osburn William O, Kensler Thomas W
Johns Hopkins University Bloomberg School of Public Health, Department of Environmental Health Sciences, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Mutat Res. 2008 Jul-Aug;659(1-2):31-9. doi: 10.1016/j.mrrev.2007.11.006. Epub 2007 Nov 23.
Human exposures to environmental toxicants have been associated with development of a number of diseases. Animal experiments have identified a number of cytoprotective enzymes under the transcriptional control of NF-E2-related factor 2 (Nrf2) including electrophile conjugation and antioxidative enzymes and enzymes responsible for the production of antioxidants, reducing equivalents and cofactors. The up-regulation of these enzymes represents an adaptive response which occurs in the face of exposure to electrophilic or oxidative compounds thereby leading to enhanced metabolism of these molecules or their reactive metabolites. This adaptive response is regulated by an interaction between Keap1 and Nrf2 in which the exposure to reactive molecules is sensed either directly by Keap1 or indirectly by cellular signaling cascades resulting in activation of Nrf2 transcriptional regulation. The Nrf2-mediated adaptive response has been shown to attenuate toxicity and carcinogenesis during electrophile or oxidative stress as well as inflammation in rodent models. The cytoprotective attributes of the Nrf2 signaling pathway have been targeted for chemoprevention as administration of Nrf2-inducing agents has been shown to result in decreased carcinogenesis in animal models and altered carcinogen metabolism in humans. On the other hand, polymorphisms in the Nrf2 signaling pathway can lead to differential susceptibility to disease while mutations in the Nrf2 signaling pathway have been shown to an effective mechanism for cancer cells to evade chemotherapy. Overall, the Nrf2 cytoprotective adaptive response has evolved to be a powerful protective strategy for organisms against exposure to environmental toxicants and may provide insight into differential disease susceptibilities across populations and responses to therapies designed to alleviate these conditions.
人类接触环境毒物与多种疾病的发生有关。动物实验已鉴定出多种受核因子E2相关因子2（Nrf2）转录调控的细胞保护酶，包括亲电物结合酶、抗氧化酶以及负责产生抗氧化剂、还原当量和辅因子的酶。这些酶的上调代表了一种适应性反应，它发生在接触亲电或氧化化合物的情况下，从而导致这些分子或其活性代谢物的代谢增强。这种适应性反应由Keap1和Nrf2之间的相互作用调节，其中亲电分子的暴露可由Keap1直接感知，或由细胞信号级联间接感知，从而导致Nrf2转录调控的激活。在啮齿动物模型中，Nrf2介导的适应性反应已被证明可减轻亲电或氧化应激以及炎症过程中的毒性和致癌作用。Nrf2信号通路的细胞保护特性已被作为化学预防的靶点，因为已证明给予诱导Nrf2的药物可导致动物模型中的致癌作用降低以及人类致癌物代谢改变。另一方面，Nrf2信号通路中的多态性可导致对疾病的易感性差异，而Nrf2信号通路中的突变已被证明是癌细胞逃避化疗的有效机制。总体而言，Nrf2细胞保护适应性反应已演变为生物体抵御环境毒物暴露的强大保护策略，并可能为不同人群对疾病的易感性差异以及对旨在缓解这些状况的治疗的反应提供见解。
