Formation of N2-tetrahydrofuranyl and N2-tetrahydropyranyl adducts in the reactions of alpha-acetoxy-N-nitrosopyrrolidine and alpha-acetoxy-N-nitrosopiperidine with DNA.
We studied the reactions with DNA of alpha-acetoxy-N-nitrosopyrrolidine (alpha-acetoxyNPYR) and alpha-acetoxy-N-nitrosopiperidine (alpha-acetoxyNPIP) in order to obtain more information on adduct formation by metabolic activation via alpha-hydroxylation of two cyclic nitrosamines, N-nitrosopyrrolidine (NPYR) and N-nitrosopiperidine (NPIP). Enzyme hydrolysis and HPLC analysis of DNA that had been reacted with unlabeled, [14C]-, or [3H]alpha- acetoxyNPYR permitted the positive identification of N2-(tetrahydrofuran-2-yl)deoxyguanosine (THF-dG). It was identified by comparison of its UV spectrum and retention time to those of a standard, by conversion upon NaBH4 treatment to N2-(4-hydroxybutyl)deoxyguanosine, and by neutral thermal hydrolysis to 2-hydroxytetrahydrofuran (THF-OH). The levels of THF-dG in DNA exceeded that of other adducts of alpha-acetoxyNPYR. Reaction of alpha-acetoxyNPIP with DNA followed by enzyme hydrolysis and HPLC analysis resulted in the positive identification of two diastereomers of N2-(3,4,5,6-tetrahydro-2H-pyran-2-yl)deoxyguanosine (THP-dG) by comparison of their retention times and UV spectra to those of standards. The levels of THP-dG were similar to those of THF-dG formed from alpha-acetoxyNPYR. Neutral thermal hydrolysis of DNA that had been reacted with alpha-acetoxyNPIP produced 2-hydroxy-3,4,5,6-tetrahydro-2H-pyran (THP-OH). Studies on the mechanism of formation of THF-dG and THP-dG indicated that stable cyclic oxonium ion-derived electrophiles could be their major precursors. Our data provide the first evidence for the formation of cyclic oxonium ion-derived DNA adducts from cyclic nitrosamines and indicate some potential differences in DNA binding between alpha-acetoxyNPYR and alpha-acetoxyNPIP.(ABSTRACT TRUNCATED AT 250 WORDS)
Wang
M
M
American Health Foundation, Valhalla, New York 10595, USA.
Young-Sciame
R
R
Chung
F L
FL
Hecht
S S
SS
D002273:Carcinogens / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000737:chemistry*; D005663:Furans / Q000737:chemistry*; D006868:Hydrolysis; D009242:N-Nitrosopyrrolidine / Q000031:analogs & derivatives* / Q000737:chemistry; D009603:Nitroso Compounds / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D011714:Pyrans / Q000737:chemistry*; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
D002273:Carcinogens; D018736:DNA Adducts; D005663:Furans; D009603:Nitroso Compounds; D010880:Piperidines; D011714:Pyrans; C078330:alpha-acetoxy-N-nitrosopiperidine; C036669:alpha-acetoxy-N-nitrosopyrrolidine; D009242:N-Nitrosopyrrolidine