Identification of paraldol-deoxyguanosine adducts in DNA reacted with crotonaldehyde

M. Wang, E. J. McIntee, G. Cheng, Y. Shi, Peter W Villalta, Stephen S Hecht

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34 Scopus citations


Crotonaldehyde (1) is a mutagen and carcinogen, but its reactions with DNA have been only partially characterized. In a previous study, we found that substantial amounts of 2-(2hydroxypropyl)-4-hydroxy-6-methyl-1,3-dioxane (paraldol, 7), the dimer of 3-hydroxybutanal (8), were released upon enzymatic or neutral thermal hydrolysis of DNA that had been allowed to react 0with crotonaldehyde. We have now characterized two paraldol-deoxyguanosine adducts in this DNA: N2-[2-(2-hydroxypropyl)-6-methyl-1,3-dioxan-4-yl]deoxyguanosine (N2-paraldoldG, 13) and N2-[2-(2-hydroxypropyl)-6-methyl-1,3-dioxan-4-yl]deoxyguanylyl-(5'-3')-thymi dine [N2-paraldol-dG-(5'-3')-thymidine, 14]. Four diastereomers of N2-paraldol-dG (13) were observed. Their overall structures were determined by 1H NMR, by MS, and by reaction of paraldol with deoxyguanosine and DNA. 1H NMR data showed that two diastereomers had all equatorial substituents in the dioxane ring, while two others had an axial 6-methyl group. Preparation of paraldol with the (R)- or (S)-configuration at the 6-position of the dioxane ring and the carbinol carbon of the 2-(2-hydroxypropyl) group allowed partial assignment of the absolute configurations of N2-paraldol-dG (13). Four diastereomers of N2-paraldol-dG-(5'-3')thymidine (14) were observed. Their overall structure was determined by 1H NMR, MS, and hydrolysis with snake venom or spleen phosphodiesterase. Reactions of nucleosides and nucleotides with paraldol demonstrated that adducts were formed only from deoxyguanosine and its monophosphates. Experiments with DNA that had been reacted with crotonaldehyde indicated that N2-paraldol-dG-containing adducts in DNA are relatively resistant to enzymatic hydrolysis. The results of this study demonstrate that the reaction of crotonaldehyde with DNA is more complex than previously recognized and that stable N2-paraldol-dG adducts are among those that should be considered in assessing mechanisms of crotonaldehyde mutagenicity and carcinogenicity.

Original languageEnglish (US)
Pages (from-to)1065-1074
Number of pages10
JournalChemical research in toxicology
Issue number10
StatePublished - 2000


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