Cellular levels and molecular dynamics simulations of estragole DNA adducts point at inefficient repair resulting from limited distortion of the double-stranded DNA helix
Autor: | Jakob D. H. Liu, Jacques Vervoort, Shuo Yang, Sebastiaan Wesseling, Matthias Diem, Chris Oostenbrink, Ivonne M.C.M. Rietjens |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
DNA Repair DNA repair efficiency DNA repair Health Toxicology and Mutagenesis Mutant Biochemie Allylbenzene Derivatives Genotoxicity and Carcinogenicity Molecular modeling and simulation Anisoles Molecular Dynamics Simulation 010501 environmental sciences Toxicology 01 natural sciences Biochemistry Mass Spectrometry Adduct DNA Adducts 03 medical and health sciences chemistry.chemical_compound Cricetulus Cricetinae Toxicity Tests DNA adduct Animals Toxicologie 0105 earth and related environmental sciences VLAG Estragole Chinese hamster ovary cell Liver cell Deoxyguanosine DNA General Medicine Rats Flavoring Agents 030104 developmental biology chemistry Carcinogens Hepatocytes Biophysics Chromatography Liquid Nucleotide excision repair |
Zdroj: | Archives of Toxicology, 94(4), 1349-1365 Archives of Toxicology 94 (2020) 4 Archives of Toxicology |
ISSN: | 0340-5761 |
Popis: | Estragole, naturally occurring in a variety of herbs and spices, can form DNA adducts after bioactivation. Estragole DNA adduct formation and repair was studied in in vitro liver cell models, and a molecular dynamics simulation was used to investigate the conformation dependent (in)efficiency of N2-(trans-isoestragol-3′-yl)-2′-deoxyguanosine (E-3′-N2-dG) DNA adduct repair. HepG2, HepaRG cells, primary rat hepatocytes and CHO cells (including CHO wild-type and three NER-deficient mutants) were exposed to 50 μM estragole or 1′-hydroxyestragole and DNA adduct formation was quantified by LC–MS immediately following exposure and after a period of repair. Results obtained from CHO cell lines indicated that NER plays a role in repair of E-3′-N2-dG adducts, however, with limited efficiency since in the CHO wt cells 80% DNA adducts remained upon 24 h repair. Inefficiency of DNA repair was also found in HepaRG cells and primary rat hepatocytes. Changes in DNA structure resulting from E-3′-N2-dG adduct formation were investigated by molecular dynamics simulations. Results from molecular dynamics simulations revealed that conformational changes in double-stranded DNA by E-3′-N2-dG adduct formation are small, providing a possible explanation for the restrained repair, which may require larger distortions in the DNA structure. NER-mediated enzymatic repair of E-3′-N2-dG DNA adducts upon exposure to estragole will be limited, providing opportunities for accumulation of damage upon repeated daily exposure. The inability of this enzymatic repair is likely due to a limited distortion of the DNA double-stranded helix resulting in inefficient activation of nucleotide excision repair. |
Databáze: | OpenAIRE |
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