Synthesis, Characterization, and Identification of New in Vitro Covalent DNA Adducts of Divinyl Sulfone, an Oxidative Metabolite of Sulfur Mustard,Chemical Research in Toxicology

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Synthesis, Characterization, and Identification of New in Vitro Covalent DNA Adducts of Divinyl Sulfone, an Oxidative Metabolite of Sulfur Mustard
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2017-10-05 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00196
Shanshan Lv ₁ , Yajiao Zhang ₁ , Bin Xu ₁ , Hua Xu ₁ , Yumei Zhao ₁ , Jia Chen ₁ , Zhongcai Gao ₁ , Jianfeng Wu ₁ , Jianwei Xie ₁

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Divinyl sulfone (DVS) is an important oxidative metabolic product of sulfur mustard (SM) in vitro and in vivo. Although DVS is not a classical blister agent, its high reactivity and toxicity induced by vinyl groups can also cause blisters like SM upon contact with the skin, eyes, and respiratory organs. The purpose of this paper was to identify whether DVS could covalently bind to DNA bases to form new DNA adducts in cells in vitro. A series of adducts were synthesized and characterized using purine, nucleoside, or DNA, separately, as starting materials. The covalent site, pattern, and relative reactivity of adduct formation were identified and discussed in detail. The results showed that five high abundance site-specific DNA adducts, including two monoadducts and three cross-linked adducts, were obtained when DNA was used as a substrate. When HaCaT cells were exposed to 30 μM of DVS, four new DNA adducts containing monoadducts and cross-linked adducts were found and identified in cells, including N3-A monoadduct, N7-G monoadduct, N7G-N7G bis-adduct, and N3A-N7G cross-linked adduct. Among them, the abundance of N3-A monoadduct was 10 times higher than that of the other three adducts. DNA adduct formation with DVS showed significant differences from that observed with SM. The observation of these new DNA adduct in vitro cells revealed that DNA damage could be also induced by DVS.

中文翻译：

芥菜的一种氧化代谢产物二乙烯基砜的新型体外共价DNA加合物的合成，表征和鉴定

二乙烯基砜（DVS）是硫芥子气（SM）的一个重要的氧化代谢产物在体外和体内。尽管DVS不是经典的起泡剂，但乙烯基引发的高反应性和毒性也会在与皮肤，眼睛和呼吸器官接触时引起SM等水泡。本文的目的是鉴定DVS是否可以共价结合到DNA碱基上以在体外细胞中形成新的DNA加合物。分别使用嘌呤，核苷或DNA作为起始原料合成和表征了一系列加合物。鉴定并详细讨论了加合物形成的共价位点，模式和相对反应性。结果表明，以DNA为底物可获得5个高丰度位点特异性DNA加合物，包括2个单加合物和3个交联的加合物。当HaCaT细胞暴露于30μMDVS时，在细胞中发现并鉴定了四个新的包含单加合物和交联加合物的DNA加合物，包括N3-A单加合物，N7-G单加合物，N7G-N7G双加合物和N3A- N7G交联加合物。其中，N3-A单加合物的丰度是其他三个加合物的十倍。用DVS形成的DNA加合物显示出与用SM观察到的显着差异。体外细胞显示，DVS也可诱导DNA损伤。

更新日期：2017-10-05

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