Analysis for N2-(pyridyloxobutyl)deoxyguanosine adducts in DNA of tissues exposed to tritium-labeled 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine.
The tobacco-specific carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are metabolically activated to DNA binding intermediates, partially via 4-(3-pyridyl)-4-oxobutanediazohydroxide (7) or related carbonium ions. Previous studies have shown that generation of 7 from 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone (11) in the presence of deoxyguanosine yields a major adduct identified as 2'-deoxy-N-[1-methyl-3-oxo-3-(3-pyridyl)propyl]guanosine (adduct 1). These results suggested that adduct 1 should be present in DNA of tissues that can metabolically activate NNK and NNN. In the present study, we evaluate the formation of adduct 1 and its structurally related straight-chain analogue 2'-deoxy-N-[4-oxo-4-(3-pyridyl)butyl]guanosine (adduct 2) in DNA of tissues of rats treated with [5-3H]NNK or [5-3H]NNN, and in DNA of nasal mucosa that had been cultured in medium containing [5-3H]NNK or [5-3H]NNN. Hepatic DNA from rats treated with [5-3H]NNK was enzymatically hydrolyzed to deoxyribonucleosides and analyzed by HPLC. One of the radioactive peaks, peak E, coeluted with adduct 1. However, treatment of peak E with NaBH4 resulted in the formation of products different from those produced by NaBH4 treatment of adduct 1, demonstrating that adduct 1 could not be detected under these conditions. Hydrolysis of peak E with acid produced 4-hydroxy-1-(3-pyridyl)-1-butanone (9), suggesting that peak E might be adduct 2. Therefore, adduct 2 was synthesized by reaction of deoxyguanosine with 1-(3-pyridyl)butane-1,4-dione (5) in the presence of NaCNBH3.(ABSTRACT TRUNCATED AT 250 WORDS)
Spratt
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Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Trushin
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Lin
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Hecht
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D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D004947:Esophagus / Q000166:cytology / Q000378:metabolism; D006868:Hydrolysis; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000166:cytology / Q000187:drug effects; D009602:Nitrosamines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D009602:Nitrosamines; C072335:N(2)-(pyridyloxobutyl)deoxyguanosine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D004247:DNA; D003849:Deoxyguanosine; C008655:N'-nitrosonornicotine