A schiff base is a major DNA adduct of crotonaldehyde

Mingyao Wang, Edward J. McIntee, Guang Cheng, Yongli Shi, Peter W. Villalta, Stephen S. Hecht

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33 Scopus citations

Abstract

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 adducts releases 2-(2-hydroxypropyl)-4-hydroxy-6-methyl-1,3-dioxane (paraldol, 12) upon hydrolysis, and these adducts are quantitatively more significant than the Michael addition adducts in vitro. In this study, we demonstrate that the major source of the paraldol-releasing DNA adducts of crotonaldehyde is a Schiff base. Reaction of crotonaldehyde with DNA, followed by treatment with NaBH3CN and enzyme hydrolysis, resulted in the formation of N2-(3-hydroxybutyl)dG (10), identified by its UV, MS, and proton NMR. Reactions of crotonaldehyde or paraldol with dG demonstrated that the Schiff base precursor to N2-(3-hydroxybutyl)dG is N2-(3-hydroxybutylidene)dG (7), identified by UV, LC-APCI-MS, and MS/MS. Four isomers of N2-(3-hydroxybutylidene)dG were observed. The (R)- and (S)-isomers were identified by reactions of chiral paraldol with dG; each existed as a pair of interconverting (E)- and (Z)-isomers. These data indicate that the structure of the major Schiff base DNA adduct in crotonaldehyde-treated DNA is N2-(3-hydroxybutylidene)dG (7). This adduct is unstable at the nucleoside level and accounts for more than 90% of the paraldol released from crotonaldehyde-treated DNA. However, the adduct is stable in DNA and therefore is a likely companion to the Michael addition adducts in human DNA.

Original languageEnglish (US)
Pages (from-to)423-430
Number of pages8
JournalChemical research in toxicology
Volume14
Issue number4
DOIs
StatePublished - May 5 2001

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