Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Arch Toxicol. 2011 Apr;85(4):273-84. doi: 10.1007/s00204-011-0675-4. Epub 2011 Mar 3.
Induction of enzymes that enhance the detoxication of chemical carcinogens has been a broadly effective strategy for chemoprevention of experimental carcinogenesis in rodent models. Several inducing agents are now in clinical trials to evaluate utility for prevention of cancers associated with unavoidable high exposures to environmental carcinogens. The successes of these pre-clinical and clinical interventions lead to studies to define the molecular basis for protection by these agents, which now include phenolic antioxidants, dithiolethiones, isothiocyanates, and triterpenoids. In the mid-1990s, the NF-E2-related factor 2 (Nrf2) transcription factor was identified as a key regulator of the inducible expression of enzymes such as glutathione S-transferases and NAD(P)H: quinone oxidoreductase in catalyzing the detoxication of reactive electrophiles and oxidants that contribute to the formation of mutations and ultimately cancers. Nrf2 is now recognized to regulate a broad cytoprotective, transcriptional response leading to prevention of damage to DNA, proteins and lipids; recognition, repair and removal of macromolecular damage; and tissue renewal following toxic assaults. Highlighting the importance of this pathway as a determinant of susceptibility to carcinogenesis, multiple studies now demonstrate enhanced incidence, multiplicity, and/or tumor burden in Nrf2-disrupted mice compared to wild-type in models of inflammation and colon cancer, bladder cancer, lung disease and cancer, stomach cancer, mammary cancer, skin cancer, and hepatocarcinogenesis.
诱导增强化学致癌物解毒的酶已成为实验性啮齿动物致癌模型中化学预防的广泛有效策略。目前有几种诱导剂正在进行临床试验，以评估其用于预防与不可避免的高暴露于环境致癌物相关的癌症的效用。这些临床前和临床干预的成功促使人们研究这些药物的保护分子基础，这些药物现在包括酚类抗氧化剂、二硫代噻唑烷、异硫氰酸盐和三萜类化合物。在 20 世纪 90 年代中期，NF-E2 相关因子 2（Nrf2）转录因子被确定为谷胱甘肽 S-转移酶和 NAD（P）H：醌氧化还原酶等酶的诱导表达的关键调节剂，这些酶在催化反应中解毒活性亲电体和氧化剂有助于突变的形成，最终导致癌症。现在认为 Nrf2 调节广泛的细胞保护、转录反应，从而防止 DNA、蛋白质和脂质受损；识别、修复和清除大分子损伤；以及在有毒攻击后组织更新。强调了该途径作为致癌易感性决定因素的重要性，多项研究表明，与野生型相比，在炎症和结肠癌、膀胱癌、肺癌和癌症、胃癌、乳腺癌、皮肤癌以及肝癌发生模型中，Nrf2 缺失小鼠的发生率、多发性和/或肿瘤负担增加。
