Metabolites of Tobacco- and E-Cigarette-Related Nitrosamines Can Drive Cu2+-Mediated DNA Oxidation.,Chemical Research in Toxicology

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Metabolites of Tobacco- and E-Cigarette-Related Nitrosamines Can Drive Cu2+-Mediated DNA Oxidation.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-07-16 , DOI: 10.1021/acs.chemrestox.0c00027
Rumasha N T Kankanamage ₁ , Abhisek Brata Ghosh ₁ , Di Jiang ₁ , Karmel Gkika ₂ , Tia Keyes ₂ , Laura A Achola ₁ , Steven Suib _{1,

3} , James F Rusling _{1,

3,

4,

5}

Affiliation

Nitrosamine metabolites resulting from cigarette smoking and E-cigarette (E-cig) vaping cause DNA damage that can lead to genotoxicity. While DNA adducts of metabolites of nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN) are well-known tobacco-related cancer biomarkers, only a few studies implicate NNN and NNK in DNA oxidation in humans. NNK and NNN were found in the urine of E-cigarette users who never smoked cigarettes. This paper proposes the first chemical pathways of DNA oxidation driven by NNK and NNN metabolites in redox reactions with Cu²⁺ and NADPH leading to reactive oxygen species (ROS). A microfluidic array with thin films of DNA and metabolic enzymes that make metabolites of NNN and NNK in the presence of Cu²⁺ and NADPH was used to estimate relative rates of DNA oxidation. Detection by electrochemiluminescence (ECL) employed a new ECL dye [Os(tpy-benz-COOH)₂]²⁺ that is selective for and sensitive to the primary DNA oxidation product 8-oxo-7,8-dihydro-2-deoxyguanosine (8-oxodG) in DNA. Enzyme–DNA films on magnetic beads were used to produce nitrosamine metabolites that enter ROS-forming redox cycles with Cu²⁺ and NADPH, and liquid chromatography–mass spectrometry (LC–MS) was used to quantify 8-oxodG and identify metabolites. ROS were detected by optical sensors. Metabolites of NNK and NNN + Cu²⁺ + NADPH generated relatively high rates of DNA oxidation. Lung is the exposure route in smoking and vaping, human lung tissue contains Cu²⁺ and NADPH, and lung microsomal enzymes gave the highest rates of DNA oxidation in this study. Also, E-cigarette vapor contains 6-fold more copper than that in cigarette smoke, which could exacerbate DNA oxidation.

中文翻译：

烟草和电子烟相关亚硝胺的代谢物可以驱动 Cu2+ 介导的 DNA 氧化。

吸烟和电子烟 (E-cig) 产生的亚硝胺代谢物会导致 DNA 损伤，从而导致基因毒性。虽然亚硝胺 4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 和N-亚硝基降烟碱 (NNN) 代谢物的 DNA 加合物是众所周知的烟草相关癌症生物标志物，但只有少数研究表明 NNN和 NNK 在人类 DNA 氧化中的作用。在从不吸烟的电子烟使用者的尿液中发现了 NNK 和 NNN。本文提出了由 NNK 和 NNN 代谢物与 Cu ²⁺和 NADPH 发生氧化还原反应产生活性氧 (ROS) 驱动的 DNA 氧化的第一个化学途径。使用具有 DNA 和代谢酶薄膜的微流体阵列（在 Cu ²⁺和 NADPH 存在下产生 NNN 和 NNK 代谢物）来估计 DNA 氧化的相对速率。电化学发光 (ECL) 检测采用了一种新的 ECL 染料 [Os(tpy-benz-COOH) ₂ ] ²⁺ ，该染料对主要 DNA 氧化产物 8-oxo-7,8-diHydro-2-deoxyguanosine 具有选择性和敏感性（ DNA 中的 8-oxodG)。磁珠上的酶-DNA 薄膜用于产生亚硝胺代谢物，这些代谢物进入与 Cu ²⁺和 NADPH 形成 ROS 的氧化还原循环，并使用液相色谱-质谱 (LC-MS) 定量 8-oxodG 并鉴定代谢物。通过光学传感器检测ROS。 NNK 和NNN + Cu ²⁺ + NADPH 的代谢物产生相对较高的DNA 氧化率。肺部是吸烟和电子烟的暴露途径，人体肺组织含有 Cu ²⁺和 NADPH，并且肺微粒体酶在本研究中给出了最高的 DNA 氧化率。此外，电子烟蒸气中的铜含量是香烟烟雾中的 6 倍，这可能会加剧 DNA 氧化。

更新日期：2020-08-17

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