Reaction of N-hydroxylamine and N-acetoxy derivatives of 2-amino-3-methylimidazolo[4,5-f]quinoline with DNA. Synthesis and identification of N-(deoxyguanosin-8-yl)-IQ.
The N-hydroxylamine of the carcinogen 2-amino-3-methylimidazolo[4,5-f]quinoline (IQ) covalently bound to calf thymus DNA at pH 7, and the binding was 11% higher under acidic conditions (pH 5). The extent of N-hydroxy-IQ binding to single-stranded polynucleotides at neutral pH was in the following order: polyguanylic acid much greater than polyadenylic acid greater than polycytidylic acid = polyuridylic acid. The binding of the carcinogen to DNA, polyguanylic acid and polyadenylic acid at neutral pH was enhanced 6-, 4- and 2-fold respectively by the presumed in situ formation of N-acetoxy-IQ from N-hydroxy-IQ and acetic anhydride. N-(Deoxyguanosin-8-yl)-IQ was synthesized by reaction at pH 7 of N-acetoxy-IQ (formed in situ with N-hydroxy-IQ and acetic anhydride) with deoxyguanosine and the structure characterized by NMR, mass spectral and UV absorption spectral analyses. Reverse phase HPLC of enzymatically hydrolyzed DNA which had been reacted with N-hydroxy-IQ in vitro showed a major adduct which was chromatographically identical to synthetic N-(deoxyguanosin-8-yl)-IQ. In addition, N-acetoxy-IQ, generated chemically by acetic anhydride or enzymatically with mammalian acetyltransferase, formed one major adduct with DNA which was chromatographically identical to the synthetic N-(deoxyguanosin-8-yl)-IQ. The results indicate that N-hydroxy-IQ and N-acetoxy-IQ react with DNA forming primarily the N-(deoxyguanosin-8-yl)-IQ adduct.
Snyderwine
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Division of Cancer Etiology, National Cancer Institute, Bethesda, MD 20892.
Roller
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Adamson
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Sato
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Thorgeirsson
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D000085:Acetates; D002273:Carcinogens; D002851:Chromatography, High Pressure Liquid; D004247:DNA; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006898:Hydroxylamines; D009682:Magnetic Resonance Spectroscopy; D011804:Quinolines / Q000138:chemical synthesis*
D000085:Acetates; D002273:Carcinogens; D006898:Hydroxylamines; D011804:Quinolines; C056105:N-(deoxyguanosin-8-yl)-2-amino-3-methylimidazolo(4,5-f)quinoline; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D004247:DNA; D003849:Deoxyguanosine