Reactivity and Mutagenicity of Endogenous DNA Oxopropenylating Agents:  Base Propenals, Malondialdehyde, and <i>N</i><sup>ε</sup>-Oxopropenyllysine

Plastaras, John P.; Riggins, James N.; Otteneder, Michael B.; Marnett, Lawrence J.

doi:10.1021/tx0001631

Cited by 80 publications

(94 citation statements)

References 35 publications

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“…Quantification of M 1 dG-The M 1 dG content of all DNA samples was measured by an immunoblot assay (14). To construct standard curves, MDA-modified DNA (calibrated against a standard provided by Prof. Lawrence Marnett, Vanderbilt University) was diluted with calf thymus DNA to give 6.6 g of DNA in 150 l of PBS followed by sonication for 15 min at 4°C, heating at 100°C for 15 min, and cooling in ice water for 10 min.…”

Section: Methodsmentioning

confidence: 99%

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Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Zhou

Taghizadeh

Dedon

2005

Journal of Biological Chemistry

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The endogenous DNA adduct, M 1 dG, has been shown to arise in vitro in reactions of dG with malondialdehyde (MDA), a product of both lipid peroxidation and 4-oxidation of deoxyribose in DNA, and with base propenals also derived from deoxyribose 4-oxidation. We now report the results of cellular studies consistent with base propenals, and not MDA, as the major source of M 1 dG under biological conditions. As a foundation for cellular studies, M 1 dG, base propenals, and MDA were quantified in purified DNA treated with oxidizing agents known to produce deoxyribose 4-oxidation. The results revealed a consistent pattern; Fe 2؉ -EDTA and ␥-radiation generated MDA but not base propenals or M 1 dG, whereas bleomycin and peroxynitrite (ONOO ؊ ) both produced M 1 dG as well as base propenals with no detectable MDA. These observations were then assessed in Escherichia coli with controlled membrane levels of polyunsaturated fatty acids (PUFA). ONOO ؊ treatment (2 mM) of cells containing no PUFA (defined medium with 18:0/stearic acid) produced 6.5 M 1 dG/10 7 deoxynucleotides and no detectable lipid peroxidation products, including MDA, as compared with 3.8 M 1 dG/ 10 7 deoxynucleotides and 0.07 g/ml lipid peroxidation products with control cells grown in a mixture of fatty acids (0.5% PUFA) mimicking Luria-Bertani medium. In cells grown with linoleic acid (18:2), the level of PUFA rose to 54% and the level of MDA rose to 0.14 g/ml, whereas M 1 dG fell to 1.4/10 7 deoxynucleotides. Parallel studies with ␥-radiation revealed levels of MDA similar to those produced by ONOO ؊ but no detectable M 1 dG. These results are consistent with base propenals as the major source of M 1 dG in this model cell system.

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Section: Methodsmentioning

confidence: 99%

“…1), also react with DNA to form M 1 dG (13), although with significantly greater efficiency than MDA (13,14). This may explain the 30 -60-fold greater mutagenicity of base propenals than MDA (14).…”

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confidence: 99%

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Zhou

Taghizadeh

Dedon

2005

Journal of Biological Chemistry

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“…8 MDA is an aldehyde capable of interacting with DNA to form 3-(2-deoxy-β-D-erythropentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M 1 dG) adducts. 9,10 Exocyclic M 1 dG adducts, if not repaired, may block cell replication and cause base pair and frameshift mutations in repeated sequences. 11,12 M 1 dG adducts have been associated with the loss of DNA methylation in the Long Interspersed Nuclear Element-1 repeated sequences, and in the promoter region of the inflammatory cytokine interleukin-6 gene.…”

Section: Introductionmentioning

confidence: 99%

Formaldehyde-induced toxicity in the nasal epithelia of workers of a plastic laminate plant

et al. 2016

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Formaldehyde is a ubiquitous volatile organic compound widely used for various industrial purposes. Formaldehyde was reclassified by the International Agency for Research on Cancer as a human carcinogen, based on sufficient evidence for a casual role for nasopharyngeal cancer. However, the mechanisms by which this compound causes nasopharyngeal cancer are not completely understood. Therefore, we have examined the formaldehyde-induced toxicity in the nasal epithelia of the workers of a plastic laminate plant in Bra, Cuneo, Piedmont region, North-Western Italy, hence in the target site for formaldehyderelated nasal carcinogenesis. We have conducted a cross-sectional study aimed at comparing the frequency of 3-(2-deoxy-β-D-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M 1 dG) adducts, a biomarker of oxidative stress and lipid peroxidation, in 50 male exposed workers and 45 male controls using 32 P-DNA post-labeling. The personal levels of formaldehyde exposure were analysed by gas-chromatography mass-spectrometry. The smoking status was estimated by measuring the concentrations of urinary cotinine by gas-chromatography mass-spectrometry. The air monitoring results showed that the exposure levels of formaldehyde were significantly greater for the plastic laminate plant workers, 211.4 ± 14.8 standard error (SE) µg m −3 , than controls, 35.2 ± 3.4 (SE) µg m −3 , P < 0.001. The levels of urinary cotinine were 1064 ± 118 ng ml −1 and 14.18 ± 2.5 ng ml −1 in smokers and non-smokers, respectively, P < 0.001. The M 1 dG adduct frequency per 10 8 normal nucleotides was significantly higher among the workers of the plastic laminate plant exposed to formaldehyde, 111.6 ± 14.3 (SE), compared to controls, 49.6 ± 3.4 (SE), P < 0.001. This significant association persisted also when personal dosimeters were used to measure the extent of indoor levels of formaldehyde exposure. No influences of smoking and age were observed across the study population. However, after categorization for occupational exposure, a significant effect was found in the controls, P = 0.018, where the levels of DNA damage were significantly correlated with the levels of urinary cotinine, regression coefficient (β) = 0.494 ± 0.000 (SE), P < 0.002. Our findings indicated that M 1 dG adducts constitute a potential mechanism of formaldehydeinduced toxicity. Persistent DNA damage contributes to the general decline of the physiological mechanisms designed to maintain cellular homeostasis.

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“…Oligonucleotide m/z (da) calcd observed 5′-GCTAGC-M 1 dG-AGTCC-3′ (9) 3680.6 3681.4 5′-TCGTT-OPdA-TTGCT-3′ (12) 3365.6 3366.8 5′-CAGTC-OPdA-CTAGA-3′ (13) 3377.6 3377.5 5′-CAGTG-OPdA-GTAGA-3′ (14) 3417.7 3418.6 5′-GCAAAAA-OPdA-AAAACATGG-3′ (15) 5304.9 5306.4 5′-TCGTT-OPdA-TTGCT-3′ (12) 5′-AGCAA--T--AACGA-5′ 46° C (43° C) 3° C 5′-CAGTC-OpdA-CTAGA-3′ (13) 3′-GTCAG T--GATCT-5′ 44° C (44° C) 0° C 5′-CAGTG-OPdA-GTAGA-3′ (14) 3′-GTCAC T--CATCT-5′ 46° C (45° C) 1° C 5′-GCAAAAA-OPdA-AAAACATGG-3′ (15) 3′-CGTTTTT--T--TTTTGTACC-5′ 55° C (56° C) −1° C 5′-GCAAAAA-OPdA-AAAACATGG-3′ (15) 3′-CGTTTTT-----TTTTGTACC-5′ 51° C (50° C) 1° C 5′-GCAAAAA-OPdA-AAAACATGG-3′ (15) 3′-CGTTTTT-----TTTGTACC-5′ 48° C (47° C) 1° C a Conditions: 100 mM NaCl, 10 mM, pH 7 sodium phosphate, 50 μM EDTA, 0.5 A 260 /mL of each oligonucleotide. The temperature was raised 1° C/ min.…”

Section: Methodsmentioning

confidence: 99%

Site-Specific Synthesis of Oligonucleotides Containing Malondialdehyde Adducts of Deoxyguanosine and Deoxyadenosine via a Postsynthetic Modification Strategy

Wang

Kozekov

Kozekova

et al. 2006

Chem. Res. Toxicol.

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Malondialdehyde (MDA) and its reactive equivalent, base propenal, are products of oxidative damage to lipids and DNA, respectively; they are mutagenic in bacterial and mammalian systems and MDA is carcinogenic in rats. MDA adducts of deoxyguanosine (M 1 dG), deoxyadenosine (OPdA) and deoxycytidine (OPdC) have been characterized. We have developed site-specific syntheses of M 1 dG and OPdA adducted oligonucleotides that rely on a post-synthetic modification strategy. This work provides an alternative route to the M 1 dG adducted oligonucleotide and to date, the only viable strategy for the site-specific synthesis of OPdA modified oligonucleotides. The stability of the modified oligonucleotides was examined by UV thermal melting studies (T m ). In contrast to the M 1 dG adduct, OPdA caused very little change in the T m .

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Reactivity and Mutagenicity of Endogenous DNA Oxopropenylating Agents: Base Propenals, Malondialdehyde, and N^ε-Oxopropenyllysine

Cited by 80 publications

References 35 publications

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Formaldehyde-induced toxicity in the nasal epithelia of workers of a plastic laminate plant

Site-Specific Synthesis of Oligonucleotides Containing Malondialdehyde Adducts of Deoxyguanosine and Deoxyadenosine via a Postsynthetic Modification Strategy

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Reactivity and Mutagenicity of Endogenous DNA Oxopropenylating Agents: Base Propenals, Malondialdehyde, and Nε-Oxopropenyllysine

Cited by 80 publications

References 35 publications

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Chemical and Biological Evidence for Base Propenals as the Major Sourceof the Endogenous M1dG Adduct in CellularDNA

Formaldehyde-induced toxicity in the nasal epithelia of workers of a plastic laminate plant

Site-Specific Synthesis of Oligonucleotides Containing Malondialdehyde Adducts of Deoxyguanosine and Deoxyadenosine via a Postsynthetic Modification Strategy

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Reactivity and Mutagenicity of Endogenous DNA Oxopropenylating Agents: Base Propenals, Malondialdehyde, and N^ε-Oxopropenyllysine