Effects of α-deuterium substitution on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in f344 rats

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its analogues substituted with deuterium at the methylene carbon, 4,4-dideutero-4-(methylnitrosamino)-1-(3-pyndyl)-1-butanone [4,4-D₂)NNK], and the methyl carbon, 4-(trideuteromethylnitrosamino)-1-(3-pyridyl)-1-butanone [(CD₃NNK) adjacent to the N-nitroso group were tested for tumorigenlcity in F344 rats. Each compound was administered by 60 s.c. injectioiis over a 20-week period such that the total doses were either 1.0 or 0.33 mmol/kg. The experiment was terminated after 104 weeks. Survival of the rats treated with the higher dose of (4,4-D₂)NNK was significantly less than survival the groups treated with the same doses of NNK or (CD₃)NNK Target tissues were liver, lung and nasal cavity for all three compounds. The higher dose of (4,4-D₂)NNK induced higher numbers of nasal tumors and malignant nasal tumors than did NNK. The lower dose of (4,4-D₂)NNK induced a higher number of nasal tumors than did NNK. No other significant differences in tumor incidence were observed. The results suggest that 4-(3-pyridyl)-4-oxobutylation DNA might be important in induction of nasal cavity tumors by NNK.