Asbestos surface provides a niche for oxidative modification
Asbestos surface provides a niche for oxidative modification
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DOI：
10.1111/j.1349-7006.2011.02087.x
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发表时间：
2011-12-01
期刊：
影响因子：
5.7
通讯作者：
Toyokuni, Shinya
中科院分区：
文献类型：
--
作者：
Nagai, Hirotaka;Ishihara, Toshikazu;Toyokuni, Shinya
石棉是一种强致癌物，与人类患恶性间皮瘤和肺癌的风险增加有关。虽然其致癌机制尚不清楚，但石棉的物理化学特性在石棉诱发疾病的发展中起着重要作用。在这些特性中，在其丰富的表面积上吸附和容纳生物分子的高能力与细胞和遗传毒性有关。之前的几项研究发现了石棉相互作用蛋白。在这里，使用基质辅助激光解吸电离飞行时间质谱法，我们系统地鉴定了吸附在商用石棉表面的各种裂解物中的蛋白质，并将其分类为以下几组：染色质/核苷酸/ rna结合蛋白、核糖体蛋白、细胞保护蛋白、细胞骨架相关蛋白、组蛋白和血红蛋白。两种富含铁的石棉类型——青石棉和亚铁石棉，其表面比温石棉更容易被原位生成的4-羟基-2-烯醛所切割和氧化修饰。相反，我们证实了温石棉的强溶血活性，发现与温石棉结合的血红蛋白，而不是二氧化硅，可以作为催化剂诱导DNA氧化损伤。这个过程产生8-羟基-2'-脱氧鸟苷，从而证实了铁在温石棉致癌性中的作用。这一证据表明，所有三种类型的石棉吸附DNA和特定的蛋白质，提供了一个生态位的氧化修饰通过催化铁。因此，考虑到石棉对组蛋白/DNA的亲和力以及石棉内化到间皮细胞中，我们的研究结果提出了一种新的假设机制，在石棉诱导的致癌过程中引起遗传改变。（癌症科学2011；102:21182125）
Asbestos is a potent carcinogen associated with increased risks of malignant mesothelioma and lung cancer in humans. Although the mechanism of carcinogenesis remains elusive, the physicochemical characteristics of asbestos play a role in the progression of asbestos-induced diseases. Among these characteristics, a high capacity to adsorb and accommodate biomolecules on its abundant surface area has been linked to cellular and genetic toxicity. Several previous studies identified asbestos-interacting proteins. Here, with the use of matrix-assisted laser desorption ionization-time of flight mass spectrometry, we systematically identified proteins from various lysates that adsorbed to the surface of commercially used asbestos and classified them into the following groups: chromatin/nucleotide/RNA-binding proteins, ribosomal proteins, cytoprotective proteins, cytoskeleton-associated proteins, histones and hemoglobin. The surfaces of crocidolite and amosite, two iron-rich types of asbestos, caused more protein scissions and oxidative modifications than that of chrysotile by in situ-generated 4-hydroxy-2-nonenal. In contrast, we confirmed the intense hemolytic activity of chrysotile and found that hemoglobin attached to chrysotile, but not silica, can work as a catalyst to induce oxidative DNA damage. This process generates 8-hydroxy-2'-deoxyguanosine and thus corroborates the involvement of iron in the carcinogenicity of chrysotile. This evidence demonstrates that all three types of asbestos adsorb DNA and specific proteins, providing a niche for oxidative modification via catalytic iron. Therefore, considering the affinity of asbestos for histones/DNA and the internalization of asbestos into mesothelial cells, our results suggest a novel hypothetical mechanism causing genetic alterations during asbestos-induced carcinogenesis. (Cancer Sci 2011; 102: 21182125)