Formation of the acrolein-derived 1,N2-propanodeoxyguanosine adducts in DNA upon reaction with 3-(N-carbethoxy-N-nitrosamino)propionaldehyde.
3-(Methylnitrosamino)propionaldehyde (MNPA) is a carcinogenic nitrosamine formed by nitrosation of arecoline, a major alkaloid in areca nut which is a constituent of betel quid. While DNA adducts of its analogue, 3-(methylnitrosamino)propionitrile, have been characterized, little is known about the structures of DNA adducts by MNPA. In this paper, we report that the acrolein-derived 1,N2-propanoguanine adducts are formed upon incubating deoxyguanosine or DNA with 3-(N-carbethoxy-N-nitrosamino)propionaldehyde, a stable carbamate precursor of the metabolically activated MNPA. The identities of these adducts were confirmed by HPLC co-migration, by their NMR and UV spectra, and by chemical properties as compared with those of the synthetic standards. Analogous results were obtained from the reaction of the carbamate with calf thymus DNA. Upon acid or enzyme hydrolysis of the carbamate-modified DNA, acrolein-guanine adducts were detected, and the levels were quantitated. Again, the identities of the adducts were verified by co-chromatography with the standards, by UV spectroscopy, or by the ring-opening with NaOH/NaBH4. Consistent with its ability to modify DNA, the carbamate was found to be mutagenic in Salmonella tester strains. These results show that acrolein is a likely metabolite from the activation of MNPA and that the formation of 1,N2-propanoguanine adducts may contribute to the mutagenicity of the carbamate of MNPA.
Chung
F L
FL
American Health Foundation, Valhalla, New York 10595.
Krzeminski
J
J
Wang
M
M
Chen
H J
HJ
Prokopczyk
B
B
D000171:Acrolein / Q000378:metabolism*; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009152:Mutagenicity Tests; D009288:Naproxen / Q000378:metabolism / Q000633:toxicity*; D009602:Nitrosamines / Q000378:metabolism / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects
C086809:3-(N-carbethoxy-N-nitrosamino)propionaldehyde; D000447:Aldehydes; D009602:Nitrosamines; C060934:1,N(2)-propanodeoxyguanosine; D009288:Naproxen; D000171:Acrolein; D004247:DNA; D003849:Deoxyguanosine