Molecular analysis of mutations induced by acrolein in human fibroblast cells using supF shuttle vector plasmids

Kawanishi, Michihiro; Matsuda, Tomonari; Nakayama, Aki; Takebe, Hiraku; Matsui, Saburo; Yagi, Takashi

doi:10.1016/s1383-5718(98)00093-x

Cited by 85 publications

(94 citation statements)

References 18 publications

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“…Unlike PAHs, where only metabolically activated forms can form adducts with DNA, Acr can directly interact with DNA and form DNA adducts (18,23). Similar to PAH-DNA adducts, Acr-DNA adducts induce mainly G:C-to-T:A transversion mutations (10,(33)(34)(35), the major type of mutations found in the p53 gene in CS-related lung cancer. Although the carcinogenicity of Acr in the lung has not been studied because of the severe toxicity associated with Acr treatment in animals, i.p.…”

Section: Acr-dg Adducts Induce G-to-t Transversion Mutations In Humanmentioning

confidence: 99%

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

Feng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

350

403

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The tumor suppressor gene p53 is frequently mutated in cigarette smoke (CS)-related lung cancer. The p53 binding pattern of carcinogenic polycyclic aromatic hydrocarbons (PAHs) found in CS coincides with the p53 mutational pattern found in lung cancer, and PAHs have thus been considered to be major culprits for lung cancer. However, compared with other carcinogenic compounds, such as aldehydes, the amount of PAHs in CS is minute. Acrolein (Acr) is abundant in CS, and it can directly adduct DNA. Acr-DNA adducts, similar to PAH-DNA adducts, induce predominantly G-to-T transversions in human cells. These findings raise the question of whether Acr-DNA adducts are responsible for p53 mutations in CS-related lung cancer. To determine the role of Acr-DNA adducts in p53 mutagenesis in CS-related lung cancer we mapped the distribution of Acr-DNA adducts at the sequence level in the p53 gene of lung cells using the UvrABC incision method in combination with ligation-mediated PCR. We found that the Acr-DNA binding pattern is similar to the p53 mutational pattern in human lung cancer. Acr preferentially binds at CpG sites, and this enhancement of binding is due to cytosine methylation at these sequences. Furthermore, we found that Acr can greatly reduce the DNA repair capacity for damage induced by benzo[a]pyrene diol epoxide. Together these results suggest that Acr is a major etiological agent for CS-related lung cancer and that it contributes to lung carcinogenesis through two detrimental effects: DNA damage and inhibition of DNA repair.DNA damage

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Section: Acr-dg Adducts Induce G-to-t Transversion Mutations In Humanmentioning

confidence: 99%

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

Feng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

350

403

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“…Both α-and γ-AcrdG are mutagenic in bacteria 16,17 and mammalian cells. 18,19 In human cells, AcrdG mainly induces mutations of G:C to T:A or A:T. 18,19 In an early report, γ-AcrdG could be detected in human tissues without Acr treatment, but α-AcrdG was not detectable in most samples. 20,21 The levels of γ-AcrdG in smokers are significantly higher than that in nonsmokers.…”

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confidence: 99%

An Ammonium Bicarbonate-Enhanced Stable Isotope Dilution UHPLC-MS/MS Method for Sensitive and Accurate Quantification of Acrolein–DNA Adducts in Human Leukocytes

et al. 2013

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Acrolein (Acr), a ubiquitous environmental pollutant, can react directly with genomic DNA to form mutagenic adducts without undergoing metabolic activation. To sensitively and accurately quantify Acr−DNA adducts (including structural isomers and stereoisomers) in human leukocytes, we developed an enhanced stable isotope dilution ultrahigh performance liquid chromatography (UHPLC)−tandem mass spectrometry (MS/MS) method using ammonium bicarbonate (NH 4 HCO 3 ), which is thermally unstable and degrades readily to carbon dioxide and ammonia in heated gas phase. Interestingly, ammonium bicarbonate (as an additive to the mobile phase) not only improves the protonation of AcrdG adducts but also suppresses the formation of MS signal-deteriorating metal−AcrdG complexes during electrospray ionization, leading to the enhancement of their MS detection by 2.3−8.7 times. In contrast, routinely used ammonium salts (ammonium acetate and ammonium formate) and formic acid do not show similar enhancement. The developed method is potentially useful for enhancing ESI-MS detection of other modified 2′-deoxyribonucleosides that have difficulty in protonation and may form excess metal complexes during electrospray ionization. The limits of detection (LODs, S/N = 3) are estimated to be about 40−80 amol. By the use of the developed method, we found that the Acr adducts of three nucleotides (dG, dA, and dC) can be detected in human leukocytes. In addition to the known γ-AcrdG, α-AcrdA is also identified as an Acr-adduct of high abundance (2.5−20 adducts per10 8 nts).

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“…The mutagenic properties of acrolein have been explored in prokaryotic and eukaryotic cells (13)(14)(15)(16). However, until recently, site-specific mutagenesis studies were not feasible due to the chemical lability of ␥-OH-PdG under conditions required for solid phase DNA synthesis.…”

mentioning

confidence: 99%

NMR Characterization of a DNA Duplex Containing the Major Acrolein-derived Deoxyguanosine Adduct γ-OH-1,-N 2-Propano-2′-deoxyguanosine

Santos

Zaliznyak

Johnson

2001

Journal of Biological Chemistry

109

179

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The environmental and endogenous mutagen acrolein reacts with cellular DNA to produce several isomeric 1,N 2 -propanodeoxyguanosine adducts. High resolution NMR spectroscopy was used to establish the structural features of the major acrolein-derived adduct, ␥-OH-1,N 2 -propano-2-deoxyguanosine. In aqueous solution, this adduct was shown to assume a ring-closed form. In contrast, when ␥-OH-1,N 2 -propano-2-deoxyguanosine pairs with dC at the center of an 11-mer oligodeoxynucleotide duplex, the exocyclic ring opens, enabling the modified base to participate in a standard Watson-Crick base pairing alignment. Analysis of the duplex spectra reveals a regular right-handed helical structure with all residues adopting an anti orientation around the glycosidic torsion angle and WatsonCrick alignments for all base pairs. We conclude from this study that formation of duplex DNA triggers the hydrolytic conversion of ␥-OH-1,N 2 -propano-2-deoxyguanosine to an open chain form, a structure that facilitates pairing with dC during DNA replication and accounts for the surprising lack of mutagenicity associated with this DNA adduct.

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Molecular analysis of mutations induced by acrolein in human fibroblast cells using supF shuttle vector plasmids

Cited by 85 publications

References 18 publications

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair

An Ammonium Bicarbonate-Enhanced Stable Isotope Dilution UHPLC-MS/MS Method for Sensitive and Accurate Quantification of Acrolein–DNA Adducts in Human Leukocytes

NMR Characterization of a DNA Duplex Containing the Major Acrolein-derived Deoxyguanosine Adduct γ-OH-1,-N 2-Propano-2′-deoxyguanosine

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