Characterization of DNA Adducts Formed in Vitro by Reaction of N-Hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline and N-Hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline at the C-8 and N2 Atoms of Guanine

Robert J. Turesky, Susan C. Rossi, Dieter H. Welti, Jackson O. Lay, Fred F. Kadlubar

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Abstract

The covalent binding of the carcinogenic N-hydroxy metabolites of 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to deoxynucleosides and DNA was investigated in vitro. Two major adducts were formed by the reaction of the Nacetoxy derivatives of IQ and MeIQx with deoxyguanosine (dG); however, no adducts were formed with deoxycytidine, deoxyadenosine, or thymidine. From proton NMR and mass spectroscopic characterization the adducts were identified as 5-(deoxyguanosin-N2-yl)-2-amino-3-methylimidazo[4,5-f]quinoline(dG-N2-IQ),N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazo-[4,5-f]quinoline (dG-C8-IQ), 5-(deoxyguanosin-N2-yl)-2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline (dG-N2-MeIQx), and N-(deoxyguanosin-8-yl)-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (dG-C8-MeIQx). The level of dG-C8 adducts was approximately 8-10 times greater than the amount of dG-N2 adducts formed from the reaction of dG with the Nacetoxy derivatives of IQ and MeIQx. The C-8-substituted dG adduct was also the major adduct formed from reactions of DNA with Nacetoxy-IQ and Nacetoxy-MeIQx. Approximately 60-80% of the bound carcinogens were recovered from DNA as dG-C8 adducts upon enzymatic digestion. The dG-N2 adducts also were detected and accounted for approximately 4% of the bound IQ and 10% of the bound MeIQx. These results suggest that the relative contributions of the nitrenium and carbenium ion resonance forms as well as DNA macromolecular structure are major determinants for DNA adduct substitution sites. Investigations on adduct conformation of 1H NMR spectroscopy revealed that the anti form is preferred for the dG-N2 adducts of IQ and MeIQx, while the syn form is preferred for the dG-C8 adducts. The possible role of these adducts in the initiation of carcinogenesis is discussed.

Original languageEnglish (US)
Pages (from-to)479-490
Number of pages12
JournalChemical research in toxicology
Volume5
Issue number4
DOIs
StatePublished - Jul 1 1992

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