Division of Pharmacology & Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India.
Free Radic Biol Med. 2011 Jul 15;51(2):257-81. doi: 10.1016/j.freeradbiomed.2011.04.008. Epub 2011 Apr 13.
This review summarizes the literature describing the molecular mechanisms of arsenic-induced oxidative stress, its relevant biomarkers, and its relation to various diseases, including preventive and therapeutic strategies. Arsenic alters multiple cellular pathways including expression of growth factors, suppression of cell cycle checkpoint proteins, promotion of and resistance to apoptosis, inhibition of DNA repair, alterations in DNA methylation, decreased immunosurveillance, and increased oxidative stress, by disturbing the pro/antioxidant balance. These alterations play prominent roles in disease manifestation, such as carcinogenicity, genotoxicity, diabetes, cardiovascular and nervous systems disorders. The exact molecular and cellular mechanisms involved in arsenic toxicity are rather unrevealed. Arsenic alters cellular glutathione levels either by utilizing this electron donor for the conversion of pentavalent to trivalent arsenicals or directly binding with it or by oxidizing glutathione via arsenic-induced free radical generation. Arsenic forms oxygen-based radicals (OH(•), O(2)(•-)) under physiological conditions by directly binding with critical thiols. As a carcinogen, it acts through epigenetic mechanisms rather than as a classical mutagen. The carcinogenic potential of arsenic may be attributed to activation of redox-sensitive transcription factors and other signaling pathways involving nuclear factor κB, activator protein-1, and p53. Modulation of cellular thiols for protection against reactive oxygen species has been used as a therapeutic strategy against arsenic. N-acetylcysteine, α-lipoic acid, vitamin E, quercetin, and a few herbal extracts show prophylactic activity against the majority of arsenic-mediated injuries in both in vitro and in vivo models. This review also updates the reader on recent advances in chelation therapy and newer therapeutic strategies suggested to treat arsenic-induced oxidative damage.
本文综述了砷诱导氧化应激的分子机制、相关生物标志物及其与各种疾病的关系，包括预防和治疗策略。砷通过干扰促氧化剂/抗氧化剂平衡，改变多种细胞途径，包括生长因子的表达、细胞周期检查点蛋白的抑制、促进和抵抗细胞凋亡、抑制 DNA 修复、DNA 甲基化的改变、免疫监视的降低以及氧化应激的增加。这些改变在疾病表现中起着重要作用，如致癌性、遗传毒性、糖尿病、心血管和神经系统疾病。砷毒性的确切分子和细胞机制尚不清楚。砷通过利用这种电子供体将五价砷转化为三价砷，或者直接与它结合，或者通过砷诱导的自由基生成氧化谷胱甘肽，来改变细胞内的谷胱甘肽水平。在生理条件下，砷通过直接与关键硫醇结合形成含氧自由基（OH(•)、O(2)(•-)）。作为一种致癌物质，它通过表观遗传机制而不是经典的突变作用。砷的致癌潜能可能归因于氧化还原敏感转录因子和其他信号通路的激活，涉及核因子 κB、激活蛋白-1 和 p53。为了防止活性氧的产生，细胞硫醇的调节已被用作对抗砷的治疗策略。N-乙酰半胱氨酸、α-硫辛酸、维生素 E、槲皮素和几种草药提取物在体外和体内模型中对大多数砷介导的损伤均显示出预防活性。本文还为读者更新了螯合疗法和新的治疗策略的最新进展，以治疗砷诱导的氧化损伤。
