Are Dinucleoside Monophosphates Relevant Models for the Study of DNA Intrastrand Cross-Link Lesions? The Example of G[8–5m]T
| Autor: | Julian Garrec, Elise Dumont |
|---|---|
| Přispěvatelé: | Institut de Physique de Rennes (IPR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie - UMR5182 (LC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2014 |
| Předmět: |
Dinucleoside Monophosphates
Guanine Genome integrity Stereochemistry Kinetics Cross-link Water General Medicine Molecular Dynamics Simulation Toxicology Nucleobase [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry chemistry.chemical_compound chemistry Dinucleoside Phosphates Thymine DNA DNA Damage |
| Zdroj: | Chemical Research in Toxicology Chemical Research in Toxicology, American Chemical Society, 2014, 27 (7), pp.1282-1293. ⟨10.1021/tx4004616⟩ Chemical Research in Toxicology, 2014, 27 (7), pp.1282-1293. ⟨10.1021/tx4004616⟩ |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/tx4004616 |
| Popis: | International audience; ortho-Quinone methides (ortho-QM) and para-quinone methides are generated by xenobiotic metabolism of numerous compounds including environmental toxins and therapeutic agents. These intermediates are highly electrophilic and have the potential to alkylate DNA. Assessing their genotoxicity can be difficult when all or some of their resulting adducts form reversibly. Stable adducts are most easily detected but are not necessarily the most prevalent products formed initially as DNA repair commences. Selective oxidation of ortho-QM-DNA adducts by bis[(trifluoroacetoxy)iodo]benzene (BTI) rapidly quenches their reversibility to prevent QM regeneration and allows for observation of the kinetic products. The resulting derivatives persist through standard enzymatic digestion, chromatography, and mass spectral analysis. The structural standards required for this approach have been synthesized and confirmed by two-dimensional NMR spectroscopy. The adducts of dA N6, dG N1, dG N2, and guanine N7 are converted to the expected para-quinol derivatives within 5 min after addition of BTI under aqueous conditions (pH 7). Concurrently, the adduct of dA N1 forms a spiro derivative comparable to that characterized previously after oxidation of the corresponding dC N3 adduct. By application of this oxidative quenching strategy, the dC N3 and dA N1 adducts have been identified as the dominant products formed by both single- and double-stranded DNA under initial conditions. As expected, however, these labile adducts dissipate within 24 h if not quenched with BTI. Still, the products favored by kinetics are responsible for inducing the first response to ortho-QM exposure in cells, and hence, they are also key to establishing the relationship between biological activity and molecular structure. |
| Databáze: | OpenAIRE |
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