Gastric DNA damage through tobacco chewing: In vitro mechanistic studies of DNA nitrite attack

Smokeless chewing tobacco or snuff has been linked to carcinogenic effects in upper aerodigestive organs. The presence of nitrite within the tobacco product is suspected to foster carcinogenic DNA mechanisms at lower pH. We studied the impact of sodium nitrite on DNA damage at single-strand conformers or hairpin loops, known to be present at fragile sites that have been shown to cause methyltransferase stalling and that can lead to chromosomal breakage. At a pH of 4.2, two base-damage products could be demonstrated at significant levels (1-5% of total nucleotides), with greater sensitivity to hairpin loops compared to a control Watson-Crick duplex. Pyrimidine-rich strands (CCG, CTG) were more reactive than purine-rich strands (CAG, CGG). The data support a mechanism for allele-specific predisposition to DNA damage. This mechanism may be of significance in gastric cancer initiation due to chewing tobacco.