We discovered the directly acting mutagenicity of the tobacco-specific nitrosamine, 4-(N-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), with UVA light (320-400 nm) in Ames bacteria and phage M13mp2 in the absence of metabolic activation. We have investigated the spectrum of mutations caused by UVA-activated NNK. The majority (57%) of induced sequence changes were comprised of GC to CG, GC to TA and GC to AT. This suggested that modification of guanine residues was responsible for these mutations. Hence, we explored the formation of 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-oxodG) and O6-methylguanine (O6meG) in the DNA. When calf thymus DNA was treated with NNK and UVA, the amount of 8-oxodG/dG and O6meG/G in the DNA increased up to 20-fold and 100-fold, respectively, compared with the untreated control. DNA strand breaks were observed following NNK and UVA treatment, and the strand breaks were suppressed in the presence of scavengers for oxygen and NO radical. The formation of NO was also observed in NNK solutions irradiated with UVA. We analyzed the photodynamic spectrum of mutation induction, 8-oxodG formation and NO formation using monochromatic radiation. The patterns of the action spectra were comparable to the absorption spectrum of NNK. We conclude that NNK may act as a photosensitizer in response to UVA to produce NO and other oxidative and alkylative intermediates following the formation of 8-oxodG and O6meG in DNA, which may lead to mutations and DNA strand breaks.
|Number of pages||10|
|Journal||Mutation Research - Genetic Toxicology and Environmental Mutagenesis|
|Publication status||Published - Aug 15 2007|
- DNA strand breaks
- Nitric oxide
ASJC Scopus subject areas
- Health, Toxicology and Mutagenesis