Reaction of alpha-acetoxy-N-nitrosopiperidine with deoxyguanosine: oxygen-dependent formation of 4-oxo-2-pentenal and a 1,N2-ethenodeoxyguanosine adduct.
The six-membered heterocyclic nitrosamine N-nitrosopiperidine (NPIP) is an esophageal carcinogen in the rat whereas its five-membered homologue N-nitrosopyrrolidine (NPYR) is a liver carcinogen. These contrasting organo-specificities may be due to differences between NPIP and NPYR in their metabolic activation to intermediates which bind to DNA. Previous studies have shown that the metabolic activation of NPYR to DNA binding products occurs through alpha-hydroxylation. DNA adducts of NPIP have not been characterized. Therefore, we began our studies by investigating the reaction of alpha-acetoxyNPIP with deoxyguanosine. A major adduct, detected by high-performance liquid chromatography with UV detection, was characterized by its UV, 1H-NMR, and MS as 7-(2-oxopropyl)-5,9-dihydro-9-oxo-3-beta-D-deoxyribofuranosylimidazo+ ++[1,2-a] purine. This 7-(2-oxopropyl)-substituted 1,N2-ethenodeoxyguanosine adduct was formed by reaction of 4-oxo-2-pentenal (3-acetylacrolein) with the 1 and N2 positions of deoxyguanosine. Since the formation of 4-oxo-2-pentenal from alpha-acetoxyNPIP was unexpected, we investigated the solvolysis of alpha-acetoxyNPIP in more detail. Major products formed in incubations of alpha-acetoxyNPIP for 7-24 h in phosphate buffer (pH 7.0) at 37 degrees C included 4-oxo-2-pentenal (11-21% yield), 4-hydroxypentanal (18-22%), and 5-hydroxypentanal (27-29%). The formation of 4-oxo-2-pentenal required O2. The results of this study demonstrate some unique features of the chemistry of alpha-acetoxyNPIP and the resulting deoxyguanosine adducts which may be related to the carcinogenic activity of NPIP.
Hecht
S S
SS
Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Young-Sciame
R
R
Chung
F L
FL
D000171:Acrolein / Q000031:analogs & derivatives* / Q000737:chemistry; D001665:Binding Sites; D002273:Carcinogens / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D009603:Nitroso Compounds / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*
D002273:Carcinogens; D009603:Nitroso Compounds; D010880:Piperidines; C054579:1,N(2)-ethenodeoxyguanosine; C078330:alpha-acetoxy-N-nitrosopiperidine; C046802:acetylacrolein; D000171:Acrolein; D004247:DNA; D003849:Deoxyguanosine