Formation of Acyclic and Cyclic Guanine Adducts in DNA Reacted with α-Acetoxy-N-nitrosopyrrolidine

Mingyao Wang, Fung Lung Chung, Stephen S. Hecht

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This paper describes the reaction of α-acetoxy-N-nitrosopyrrolidine with DNA to produce six adducts: two new acyclic adducts, 7-(4-oxobutyl)guanine (6) and 7-(3-carboxypropyl)guanine (7), and four cyclic adducts—the exocyclic 7, 8-guanine adducts 5, 11, and 12 and an exocyclic 1, N2-guanine adduct 13—which we have previously characterized. The initial purpose of this study was to carry out an independent synthesis to verify the structure of adduct 5, which is formed in liver DNA of rats treated with N-nitrosopyrrolidine. This was accomplished by the reaction of 2', 3', 5'-triacetylguanosine with 4-iodobutyraldehyde. This reaction also produced 7-(4-oxobutyl)guanine (6), which underwent air oxidation to 7. The new adducts were characterized by their proton NMR, UV, and mass spectral properties, by chemical transformations, and by independent syntheses. The six adduct standards were used to develop HPLC systems for their analysis as products of the reaction of α-acetoxy-N-nitrosopyrrolidine with DNA. Studies on their rates of formation and stability in DNA were carried out. The major products were 7-(4-oxobutyl)guanine (6) and the exocyclic 7, 8-guanine adduct 5, which apparently were both formed mainly by reaction with DNA of 4-oxobutanediazohydroxide (4). Their concentrations were maximal after 6 h and subsequently decreased due to depurination. Little evidence was obtained for cyclization of 6 to 5, at the base level or in DNA. The concentrations of adducts 11–13, which were formed by reaction with DNA of crotonaldehyde (10), increased gradually over the 36-h time period studied. The results of this study provide strong support for the proposed mechanism of DNA adduction by α-hydroxylation of the hepatocarcinogen N-nitrosopyrrolidine.

Original languageEnglish (US)
Pages (from-to)423-428
Number of pages6
JournalChemical research in toxicology
Issue number6
StatePublished - Nov 1 1989


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