Mutagenesis by Acrolein-Derived Propanodeoxyguanosine Adducts in Human Cells

Yang, In Young; Chan, Grace; Miller, Holly; Huang, Yanhe; Torres, Maria Cecilia de Araujo Rodrigues; Johnson, Francis; Moriya, Masaaki

doi:10.1021/bi0264723

Cited by 98 publications

(153 citation statements)

References 26 publications

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“…The data reported here, together with the results of Feng et al demonstrating that it causes DNA damage at mutational hot spots in the p53 gene (3), suggest involvement. Furthermore, adduct 3 has been shown to be mutagenic in human cells, causing G to T transversions (17), and we have shown that this adduct is present in human lung (8). However, levels of adducts 3 and 4 in human lung were unrelated to smoking status in our study, although the number of subjects was small.…”

Section: Discussioncontrasting

confidence: 66%

Quantitation of Acrolein-Derived (3-Hydroxypropyl)mercapturic Acid in Human Urine by Liquid Chromatography−Atmospheric Pressure Chemical Ionization Tandem Mass Spectrometry: Effects of Cigarette Smoking

Carmella

Chen

Zhang

et al. 2007

Chem. Res. Toxicol.

141

149

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Recently published data suggest that acrolein (1), a toxic but weakly carcinogenic constituent of cigarette smoke, may be involved as a causative factor for the mutations frequently observed in the p53 tumor suppressor gene in lung cancer in smokers. Biomarkers are needed to further assess the possible relationship between acrolein uptake and cancer. In this study, we analyzed 3-hydroxypropylmercapturic acid (3-HPMA, 2) in human urine. 3-HPMA is a major metabolite of acrolein in laboratory animals. The method employs [ 13 C 3 ]3-HPMA as internal standard, with analysis and quantitation by LC-APCI-MS/MS-SRM. Clean, readily quantifiable chromatograms were obtained. The method was accurate and precise and required only 0.1 mL of urine. Median levels of 3-HPMA were significantly higher (2900 pmol/mg creatinine, N = 35) in smokers than in non-smokers (683 pmol/mg creatinine, N = 21) (P = 0.0002). The effect of smoking was further assessed by determining levels of 3-HPMA before and after a 4 week smoking cessation period. There was a significant 78% decrease in median levels of urinary 3-HPMA after cessation (P < 0.0001). The relationship between levels of urinary 3-HPMA and those of acrolein-derived 1,N 2 -propanodeoxyguanosine (PdG) adducts in lung was investigated in 14 smokers. There was a significant inverse relationship between urinary 3-HPMA and α-hydroxy-PdG (3) but not γ-hydroxyPdG (4) or total adduct levels. The results of this study clearly demonstrate that acrolein uptake in smokers is significantly higher than in non-smokers, and underline the need for further investigation of the possible relationship of acrolein uptake to lung cancer.

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Section: Discussioncontrasting

confidence: 66%

Quantitation of Acrolein-Derived (3-Hydroxypropyl)mercapturic Acid in Human Urine by Liquid Chromatography−Atmospheric Pressure Chemical Ionization Tandem Mass Spectrometry: Effects of Cigarette Smoking

Carmella

Chen

Zhang

et al. 2007

Chem. Res. Toxicol.

141

149

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“…Although it is a minor adduct, α-AcrdG is >10 times more mutagenic than γ-AcrdG. 37 Surprisingly, the signal Figure 3. The typical ESI-MS spectra of AcrdG isomers were obtained when different additives to the mobile phase were used.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

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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“…Both isomeric adducts were shown to induce base substitutions with G→C transversions predominating. α-Hydroxy-PdG gave rise to a higher miscoding frequency when incorporated into DNA of human xeroderma pigmentosum A cells [86,87]. HydroxyPdG adducts have been detected in liver tissue DNA of humans and rodents without carcinogen treatment [88].…”

Section: Adduction Of Acrolein To Dnamentioning

confidence: 99%

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

Stevens

Maier

2008

Molecular Nutrition Food Res

618

634

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Acrolein (2-propenal) is ubiquitously present in (cooked) foods and in the environment. It is formed from carbohydrates, vegetable oils and animal fats, amino acids during heating of foods, and by combustion of petroleum fuels and biodiesel. Chemical reactions responsible for release of acrolein include heat-induced dehydration of glycerol, retro-aldol cleavage of dehydrated carbohydrates, lipid peroxidation of polyunsaturated fatty acids, and Strecker degradation of methionine and threonine. Smoking of tobacco products equals or exceeds the total human exposure to acrolein from all other sources. The main endogenous sources of acrolein are myeloperoxidase-mediated degradation of threonine and amine oxidase-mediated degradation of spermine and spermidine, which may constitute a significant source of acrolein in situations of oxidative stress and inflammation. Acrolein is metabolized by conjugation with glutathione and excreted in the urine as mercapturic acid metabolites. Acrolein forms Michael adducts with ascorbic acid in vitro, but the biological relevance of this reaction is not clear. The biological effects of acrolein are a consequence of its reactivity towards biological nucleophiles such as guanine in DNA and cysteine, lysine, histidine, and arginine residues in critical regions of nuclear factors, proteases, and other proteins. Acrolein adduction disrupts the function of these biomacromolecules which may result in mutations, altered gene transcription, and modulation of apoptosis.

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Mutagenesis by Acrolein-Derived Propanodeoxyguanosine Adducts in Human Cells

Cited by 98 publications

References 26 publications

Quantitation of Acrolein-Derived (3-Hydroxypropyl)mercapturic Acid in Human Urine by Liquid Chromatography−Atmospheric Pressure Chemical Ionization Tandem Mass Spectrometry: Effects of Cigarette Smoking

Quantitation of Acrolein-Derived (3-Hydroxypropyl)mercapturic Acid in Human Urine by Liquid Chromatography−Atmospheric Pressure Chemical Ionization Tandem Mass Spectrometry: Effects of Cigarette Smoking

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

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

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