Quantitation of 1,<i>N</i><sup>6</sup>-Ethenoadenine in Rat Urine by Immunoaffinity Extraction Combined with Liquid Chromatography/Electrospray Ionization Mass Spectrometry

Yen, Ten‐Yang; Holt, Sharon; Sangaiah, R.; Gold, A.; Swenberg, James A.

doi:10.1021/tx9800194

Cited by 20 publications

(24 citation statements)

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“…The elimination of these adducts in urine has generally been attributed to their removal from DNA as base adducts. Interestingly, 1, N 6 -ε-dA has also been detected in rat urine (7). On the basis of our results, 1, N 6 -ε-Ade may be the best target for quantification in urine samples.…”

Section: Discussionmentioning

confidence: 99%

Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

et al. 2009

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Non-invasive strategies for the analysis of endogenous DNA damage are of interest for the purpose of monitoring genomic exposure to biologically produced chemicals. We have focused our research on the biological processing of DNA adducts and how this may impact the observed products in biological matrixes. Preliminary research has revealed that pyrimidopurinone DNA adducts are subject to enzymatic oxidation in vitro and in vivo and that base adducts are better substrates for oxidation than the corresponding 2′-deoxynucleosides. We tested the possibility that structurally similar exocyclic base adducts may be good candidates for enzymatic oxidation in vitro. We investigated the in vitro oxidation of several endogenously occurring etheno adducts [1,N2-ε-guanine (1,N2-ε-Gua), N2,3-ε-Gua, heptanone-1,N2-ε-Gua, 1,N6-ε-adenine (1,N6-ε-Ade), and 3,N4-ε-cytosine (3,N4-ε-Cyt)] and their corresponding 2′-deoxynucleosides. Both 1,N2-ε-Gua and heptanone-1,N2-ε-Gua were substrates for enzymatic oxidation in rat liver cytosol; heteronuclear NMR experiments revealed that oxidation occurred on the imidazole ring of each substrate. In contrast, the partially or fully saturated pyrimidopurinone analogues [i.e., 5,6-dihydro-M1G and 1,N2-propanoguanine (PGua)] and their 2′-deoxynucleoside derivatives were not oxidized. The 2′-deoxynucleoside adducts, 1,N2-ε-dG and 1,N6-ε-dA, underwent glycolytic cleavage in rat liver cytosol. Together, these data suggest that multiple exocyclic adducts undergo oxidation and glycolytic cleavage in vitro in rat liver cytosol, in some instances in succession. These multiple pathways of biotransformation produce an array of products. Thus, the biotransformation of exocyclic adducts may lead to an additional class of biomarkers suitable for use in animal and human studies.

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Section: Discussionmentioning

confidence: 99%

Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

et al. 2009

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“…Accordingly, several laboratories have developed analytical methodologies to assess adduct levels in biological matrixes a Expressed as means ( SD. (12)(13)(14)(15)(16). The appearance of adducts in urine is typically attributed to repair-dependent removal from DNA (12,16,25).…”

Section: Discussionmentioning

confidence: 99%

“…(12)(13)(14)(15)(16). The appearance of adducts in urine is typically attributed to repair-dependent removal from DNA (12,16,25). However, it should be noted that urinary analysis is an indirect method of assessment, and the true origins of the adducts are unknown.…”

Section: Discussionmentioning

confidence: 99%

Monitoring in Vivo Metabolism and Elimination of the Endogenous DNA Adduct, M₁dG {3-(2-Deoxy-β-d-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one}, by Accelerator Mass Spectrometry

Knutson

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Liberman

et al. 2008

Chem. Res. Toxicol.

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Our laboratory is investigating the in vitro and in vivo metabolic processing of endogenously formed DNA adducts as a means of evaluating candidate urinary biomarkers. In particular, we have focused our studies on the metabolism and disposition of the peroxidation-derived pyrimidopurinone deoxyguanosine (dG) adduct, 3-(2-deoxy-beta-D-erythro-pentofuranosyl)pyrimido[1,2-R]purin-10(3H)-one (M1dG), and its principal metabolite, 6-oxo-M1dG. We now report the metabolic processing of M1dG at concentrations 4-8 orders of magnitude lower in concentration than previously analyzed, by the use of accelerator mass spectrometry analysis. Administration of 2.0 nCi/kg [14C]M1dG resulted in 49% of the 14C recovered in urine, whereas 51% was recovered in feces. In urine samples, approximately 40% of the 14C corresponded to the metabolite, 6-oxo-M1dG. Following iv administration of 0.5 and 54 pCi/kg [14C]M1dG, approximately 25% of the urinary recovery corresponded to the metabolite, 6-oxo-M1dG. Thus, upon administration of trace amounts of M1dG, a significant percentage of 6-oxo-M1dG was produced, suggesting that 6-oxo-M1dG maybe a useful urinary marker of exposure to endogenous oxidative damage.

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“…1 Their targeting sites are almost all localized between the exocyclic nitrogen and one of its neighboring ring nitrogen atoms, which give rise to the formation of 1,N 2 -and 3,N 2 -ethenoguanine (eGua), 1,N 6 -ethenoadenine (eAde), and 3,N 4 -ethenocytosine (eCyt). [39][40][41] In addition, as one of the most abundant products formed from lipid peroxidation, malondialdehyde (MDA) can also react with the N1 and N 2 atoms of guanine to produce an exocyclic adduct, pyrimido[1,2-a]purin-10(3H)-one (M 1 G, structure shown in Fig. 2).…”

Section: Reactive Sites On Nucleobasesmentioning

confidence: 99%

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

2015

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Exogenous and endogenous sources of chemical species can react, directly or after metabolic activation, with DNA to yield DNA adducts. If not repaired, DNA adducts may compromise cellular functions by blocking DNA replication and/or inducing mutations. Unambiguous identification of the structures and accurate measurements of the levels of DNA adducts in cellular and tissue DNA constitute the first and important step towards understanding the biological consequences of these adducts. The advances in mass spectrometry (MS) instrumentation in the past 2–3 decades have rendered MS an important tool for structure elucidation, quantification, and revelation of the biological consequences of DNA adducts. In this review, we summarized the development of MS techniques on these fronts for DNA adduct analysis. We placed our emphasis of discussion on sample preparation, the combination of MS with gas chromatography-or liquid chromatography (LC)-based separation techniques for the quantitative measurement of DNA adducts, and the use of LC-MS along with molecular biology tools for understanding the human health consequences of DNA adducts. The applications of mass spectrometry-based DNA adduct analysis for predicting the therapeutic outcome of anti-cancer agents, for monitoring the human exposure to endogenous and environmental genotoxic agents, and for DNA repair studies were also discussed.

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Quantitation of 1,N⁶-Ethenoadenine in Rat Urine by Immunoaffinity Extraction Combined with Liquid Chromatography/Electrospray Ionization Mass Spectrometry

Cited by 20 publications

References 24 publications

Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

Monitoring in Vivo Metabolism and Elimination of the Endogenous DNA Adduct, M₁dG {3-(2-Deoxy-β-d-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one}, by Accelerator Mass Spectrometry

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

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Quantitation of 1,N6-Ethenoadenine in Rat Urine by Immunoaffinity Extraction Combined with Liquid Chromatography/Electrospray Ionization Mass Spectrometry

Cited by 20 publications

References 24 publications

Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

Oxidation and Glycolytic Cleavage of Etheno and Propano DNA Base Adducts

Monitoring in Vivo Metabolism and Elimination of the Endogenous DNA Adduct, M1dG {3-(2-Deoxy-β-d-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one}, by Accelerator Mass Spectrometry

Mass spectrometry for the assessment of the occurrence and biological consequences of DNA adducts

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Product

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Quantitation of 1,N⁶-Ethenoadenine in Rat Urine by Immunoaffinity Extraction Combined with Liquid Chromatography/Electrospray Ionization Mass Spectrometry

Monitoring in Vivo Metabolism and Elimination of the Endogenous DNA Adduct, M₁dG {3-(2-Deoxy-β-d-erythro-pentofuranosyl)pyrimido[1,2-α]purin-10(3H)-one}, by Accelerator Mass Spectrometry