Metabolites of Tobacco- and E-Cigarette-Related Nitrosamines Can Drive Cu2+-Mediated DNA Oxidation

Kankanamage, Rumasha N. T.; Ghosh, Abhisek Brata; Jiang, Di; Gkika, Karmel; Keyes, Tia; Achola, Laura A.; Suib, Steven; Rusling, James F.

doi:10.1021/acs.chemrestox.0c00027

Metabolites of Tobacco- and E-Cigarette-Related Nitrosamines Can Drive Cu²⁺-Mediated DNA Oxidation

Journal Article · Thu Jul 16 00:00:00 EDT 2020 · Chemical Research in Toxicology

DOI:https://doi.org/10.1021/acs.chemrestox.0c00027· OSTI ID:1837950

Kankanamage, Rumasha N. T. ^[1]; Ghosh, Abhisek Brata ^[2]; Jiang, Di ^[2]; Gkika, Karmel ^[3]; ^[3]; Achola, Laura A. ^[2]; ^[4]; ^[5]

Univ. of Connecticut, Storrs, CT (United States); Univ of Connecticut
Univ. of Connecticut, Storrs, CT (United States)
Dublin City Univ. (Ireland)
Univ. of Connecticut, Storrs, CT (United States); Inst. of Material Science, Storrs, CT (United States)
Univ. of Connecticut, Storrs, CT (United States); Inst. of Material Science, Storrs, CT (United States); UConn Health, Farmington, CT (United States); National Univ. of Ireland at Galway (Ireland)

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. Furthermore, E-cigarette vapor contains 6-fold more copper than that in cigarette smoke, which could exacerbate DNA oxidation.

View Accepted Manuscript (DOE)

Research Organization:: Univ. of Connecticut, Storrs, CT (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: FG02-86ER13622

OSTI ID:: 1837950

Journal Information:: Chemical Research in Toxicology, Journal Name: Chemical Research in Toxicology Journal Issue: 8 Vol. 33; ISSN 0893-228X

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Metabolites of Tobacco- and E-Cigarette-Related Nitrosamines Can Drive Cu2+-Mediated DNA Oxidation

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Metabolites of Tobacco- and E-Cigarette-Related Nitrosamines Can Drive Cu²⁺-Mediated DNA Oxidation