Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway.
Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway.
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DOI：
10.1002/jbt.21463
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发表时间：
2013-02
影响因子：
3.6
通讯作者：
Zhang, Donna D.
中科院分区：
文献类型：
--
作者：
Lau, Alexandria;Whitman, Samantha A.;Jaramillo, Melba C.;Zhang, Donna D.
砷存在于环境中，由于其毒性和致癌性，已成为全球性的健康问题。然而，砷发挥其毒性作用的具体机制尚未完全阐明。转录因子核因子（红细胞衍生2）样2（Nrf 2）已被认为是对毒性损伤的细胞防御机制的主要调节因子。本综述强调了研究表明，砷激活Nrf 2-Keap 1抗氧化剂途径的一个独特的机制，从天然化合物，如萝卜硫素（SF）中发现的西兰花芽或叔丁基羟基醌（tBHQ），天然抗氧化剂通常用作食品防腐剂。证据还表明，砷抑制Nrf 2激活，并可能模拟Nrf 2的组成性激活，这已在几种人类癌症中发现，由于Nrf 2-Keap 1轴的破坏。目前的文献强烈表明，砷激活Nrf 2可能会导致而不是防止砷毒性和致癌性。还将讨论已知的Nrf 2活化剂，如天然化学预防化合物SF和硫辛酸，保护免受砷引起的有害影响的机制。这些发现将为进一步了解砷如何促进延长的Nrf 2反应提供见解，这将导致识别新的分子标记物并开发用于预防或干预砷诱导疾病的合理疗法。国家环境健康科学研究所（NIEHS）杰出新环境科学家（ONES）奖提供了一个机会来审查砷毒理学和Nrf 2生物学领域的进展。大部分资金已经导致（1）砷通过与其他Nrf 2激活剂（例如萝卜硫烷和叔丁基对苯二酚）不同的机制激活Nrf 2途径的新发现，（2）通过化学预防化合物激活Nrf 2在体外和体内保护免受砷毒性和致癌性，（3）通过破坏Keap 1介导的负调节而组成性激活Nrf 2有助于癌症和化学抗性，（4）p62介导的Keap 1隔离激活Nrf 2途径，砷可能通过p62依赖性机制激活Nrf 2。所有这些发现都已发表，并在本综述中进行了讨论。该奖项为我的实验室进一步研究调节Nrf 2途径的分子机制以及它如何在砷毒性中发挥不可或缺的作用奠定了基础。此外，了解砷毒性和致癌性背后的生物学将有助于发现预防或控制砷介导的不良反应的潜在策略。
Arsenic is present in the environment and has become a worldwide health concern due to its toxicity and carcinogenicity. However, the specific mechanism(s) by which arsenic elicits its toxic effects has yet to be fully elucidated. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been recognized as the master regulator of a cellular defense mechanism against toxic insults. This review highlights studies demonstrating that arsenic activates the Nrf2-Keap1 antioxidant pathway by a distinct mechanism from that of natural compounds such as sulforaphane (SF) found in broccoli sprouts or tert-butylhyrdoquinone (tBHQ), a natural antioxidant commonly used as a food preservative. Evidence also suggests that arsenic prolongs Nrf2 activation and may mimic constitutive activation of Nrf2, which has been found in several human cancers due to disruption of the Nrf2-Keap1 axis. The current literature strongly suggests that activation of Nrf2 by arsenic potentially contributes to, rather than protects against, arsenic toxicity and carcinogenicity. The mechanism(s) by which known Nrf2 activators, such as the natural chemopreventive compounds SF and lipoic acid, protect against the deleterious effects caused by arsenic will also be discussed. These findings will provide insight to further understand how arsenic promotes a prolonged Nrf2 response, which will lead to the identification of novel molecular markers and development of rational therapies for the prevention or intervention of arsenic-induced diseases. The National Institute of Environmental Health Science (NIEHS) Outstanding New Environmental Scientist (ONES) award has provided the opportunity to review the progress both in the fields of arsenic toxicology and Nrf2 biology. Much of the funding has led to (1) the novel discovery that arsenic activates the Nrf2 pathway by a mechanism different to that of other Nrf2 activators, such as sulforaphane and tert-butylhydroquinone, (2) activation of Nrf2 by chemopreventive compounds protects against arsenic toxicity and carcinogenicity both in vitro and in vivo, (3) constitutive activation of Nrf2 by disrupting Keap1-mediated negative regulation contributes to cancer and chemoresistance, (4) p62-mediated sequestration of Keap1 activates the Nrf2 pathway, and (5) arsenic-mediated Nrf2 activation may be through a p62-dependent mechanism. All of these findings have been published and are discussed in this review. This award has laid the foundation for my laboratory to further investigate the molecular mechanism(s) that regulate the Nrf2 pathway and how it may play an integral role in arsenic toxicity. Moreover, understanding the biology behind arsenic toxicity and carcinogenicity will help in the discovery of potential strategies to prevent or control arsenic-mediated adverse effects.
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影响因子：
3.8
作者：
Jiang T;Huang Z;Chan JY;Zhang DD
通讯作者：
Zhang DD
影响因子：
6.6
作者：
Massrieh, W;Derjuga, A;Blank, V
通讯作者：
Blank, V
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
3.8
作者：
Hughes, Michael F.;Beck, Barbara D.;Thomas, David J.
通讯作者：
Thomas, David J.
影响因子：
3.6
作者：
He, Xiaoqing;Ma, Qiang
通讯作者：
Ma, Qiang