- A schiff base is a major DNA adduct of crotonaldehyde
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Previous studies have demonstrated that the reaction of crotonaldehyde with DNA produces Michael addition products, and these have been detected in human tissues as well as tissues of untreated laboratory animals. A second class of crotonaldehyde - DNA ad
- Wang, Mingyao,McIntee, Edward J.,Cheng, Guang,Shi, Yongli,Villalta, Peter W.,Hecht, Stephen S.
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- Reactions of 2,6-dimethyl-1,3-dioxane-4-ol (aldoxane) with deoxyguanosine and DNA
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In a recent study, we identified several new DNA adducts of the carcinogen acetaldehyde, including N2-(2,6-dimethyl-1,3-dioxan-4-yl)deoxyguanosine (N2-aldoxane-dG, 2). Our goal in this study was to investigate further the formation of 2 by allowing 2,6-dimethyl-1,3-dioxane-4-ol (aldoxane, 5) to react with dG and DNA. Aldoxane is readily formed by trimerization of acetaldehyde. The reaction of aldoxane with dG and DNA produced diastereomers of N2-aldoxane-dG (2) as observed in the reactions of acetaldehyde with dG and DNA, supporting the intermediacy of aldoxane in their formation. Unexpectedly, however, an array of other adducts was formed in these reactions, including 3-(2-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2- a]purine-10(3H)one (3), 2-amino-7,8-dihydro-8-hydroxy-6-methyl-3H-pyrrolo[2,1-f] purine-4(6H)one (13), N2-(3-hydroxybutylidene)dG (9), N2-[(2-hydroxypropyl)-6-methyl-1,3-dioxane-4-yl]dG (14), and N2-ethylidene-dG (1). Adduct 1 was the major product and was found to be quite stable in DNA. The adducts result from a cascade of aldehydes, e.g., 2-butenal (crotonaldehyde, 12), 3-hydroxybutanal (7) and its dimer (2-hydroxypropyl)-6-methyl-1,3-dioxane-4-ol (paraldol, 6), and acetaldehyde, produced from aldoxane under the reaction conditions. The reactions of aldoxane with dG and DNA were compared with those of paraldol. The paraldol reactions gave products resulting from reactions of dG and DNA with paraldol, 3-hydroxybutanal, and crotonaldehyde (adducts 3, 13, and 9) but the products of the aldoxane and acetaldehyde reactions (adducts 1 and 2) were not observed, indicating that paraldol is more stable under the reaction conditions than is aldoxane. The results of this study provide new insights about the formation of DNA adducts from aldehydes via condensation products of the latter.
- Wang,McIntee,Cheng,Shi,Villalta,Hecht
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- (E)-2-hexenal-induced DNA damage and formation of cyclic 1,N2-(1,3- propano)-2'-deoxyguanosine adducts in mammalian cells
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(E)-2-Hexenal (hexenal), a natural flavor compound, acts as directly genotoxic agent and forms cyclic 1,N2-propano adducts with deoxyguanosine. Formation of this adduct in isolated DNA and in cells was studied with a modified 32P-postlabeling procedure including HPLC separation, nuclease P1 enrichment, two-dimensional TLC of adducted nucleotide bisphosphates on PEI- cellulose, and quantification of adduct spots by liquid scintillation counting. Adduct formation with the more reactive crotonaldehyde was included for comparison. Synthesized adducted dG-3'-phosphates served as external standards for identification and quantification. In calf thymus DNA, hexenal (0.2 mM) shows a time dependent formation of adducts, yielding 1.55 pmol/μmol of DNA at 5 h incubation. With crotonaldehyde (0.2 mM) the adduct rate was about 10-fold higher. Hexenal also generated 1,N2-propano-dG adducts in the human lymphoblastoid Namalva cell line (0.2 mM, 1 h, 86 fmol/μmol of DNA) and in primary rat colon mucosa cells (0.4 mM, 30 min, 50 fmol/μmol of DNA). In primary colon mucosa cells from rats and humans, hexenal and crotonaldehyde (0.4 mM, 30 min) induced DNA damage, detected by single cell microgel electrophoresis (comet assay). In primary rat gastric mucosa cells, hexenal was only weakly active, inducing detectable DNA damage in 20% of cells at 0.8 mM concentration. In contrast, primary mucosa cells from rat esophagus were as sensitive as colon cells. After single oral application of hexenal to rats (up to 320 mg/kg body wt) DNA damage was not detectable in gastrointestinal mucosa. Analysis of hexenal in selected flavored foods revealed concentrations up to 14 ppm (0.14 mM) that are comparable to its natural occurrence in some fruits and vegetables (up to 30 ppm). Thus, the concentration range selected for the toxicological studies described here clearly is relevant: Hexenal, at concentrations found in food, exerts genotoxic effects in cells from rat and human gastrointestinal tract.
- Goelzer, Petra,Janzowski, Christine,Pool-Zobel, Beatrice L.,Eisenbrand, Gerhard
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- A convenient preparative method for the 1,N2-cyclic adducts of guanine nucleosides and nucleotides with crotonaldehyde
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The treatment of guanine nucleosides and nucleotides with excess crotonaldehyde in pH 8.0 phosphate buffer containing an equimolar amount of L-arginine at 50°C for 2h resulted in the selective formation of the corresponding cyclic 1,N2-propano
- Sako, Magoichi,Yaekura, Isamu
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- Identification of DNA adducts of acetaldehyde
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Acetaldehyde is a mutagen and carcinogen which occurs widely in the human environment, sometimes in considerable amounts, but little is known about its reactions with DNA. In this study, we identified three new types of stable acetaldehyde DNA adducts, including an interstrand cross-link. These were formed in addition to the previously characterized N2-ethylidenedeoxyguanosine. Acetaldehyde was allowed to react with calf thymus DNA or deoxyguanosine. The DNA was isolated and hydrolyzed enzymatically; in some cases, the DNA was first treated with NaBH3CN. Reaction mixtures were analyzed by HPLC, and adducts were isolated and characterized by UV, 1H NMR, and MS. The major adduct was N2-ethylidenedeoxyguanosine (1), which was identified as N2-ethyldeoxyguanosine (7) after treatment of the DNA with NaBH3CN. The new acetaldehyde adducts were 3-(2-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-hydroxy-6-methylpyrimido[1,2-α]pu rine-10(3H)one (9), 3-(2-deoxyribos-1-yl)-5,6,7,8-tetrahydro-8-(N2-deoxyguanosyl)- 6-methylpyrimido[1,2-α]purine-10(3H)one (12), and N2-(2,6-dimethyl-1,3-dioxan-4-yl)deoxyguanosine (11). Adduct 9 has been previously identified in reactions of crotonaldehyde with DNA. However, the distribution of diastereomers was different in the acetaldehyde and crotonaldehyde reactions, indicating that the formation of 9 from acetaldehyde does not proceed through crotonaldehyde. Adduct 12 is an interstrand cross-link. Although previous evidence indicates the formation of cross-links in DNA reacted with acetaldehyde, this is the first reported structural characterization of such an adduct. This adduct is also found in crotonaldehyde-deoxyguanosine reactions, but in a diastereomeric ratio different than that observed here. A common intermediate, N2-(4-oxobut-2-yl)deoxyguanosine (6), is proposed to be involved in formation of adducts 9 and 12. Adduct 11 is produced ultimately from 3-hydroxybutanal, the major aldol condensation product of acetaldehyde. Levels of adducts 9, 11, and 12 were less than 10% of those of N2-ethylidenedeoxyguanosine (1) in reactions of acetaldehyde with DNA. As nucleosides, adducts 9, 11, and 12 were stable, whereas N2-ethylidenedeoxyguanosine (1) had a half-life of 5 min. These new stable adducts of acetaldehyde may be involved in determination of its mutagenic and carcinogenic properties.
- Wang,McIntee,Cheng,Shi,Villalta,Hecht
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- Smooth and selective formation of the cyclic 1,N2-propano adducts in the reactions of guanine nucleosides and nucleotides with acetaldehyde
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The treatment of guanine nucleosides and nucleotides with excess acetaldehyde in pH 8.0 phosphate buffer containing a basic amino acid such as arginine and lysine resulted in the smooth and selective formation of the corresponding cyclic 1,N2-propano adducts even under mild conditions.
- Sako, Magoichi,Yaekura, Isamu,Deyashiki, Yoshihiro
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p. 6701 - 6703
(2007/10/03)
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