Nitroso transfer from alpha-nitrosamino aldehydes: implications for carcinogenesis

Six alkylnitrosamino ethanols (R-N(NO)-CH2CH2OH; R = Me, nBu, sBu, iBu, tBu, HOCH2CH2-), including the potent carcinogen N-nitrosodiethanolamine, have been shown to undergo efficient liver alcohol dehydrogenase catalyzed oxidation to their corresponding alpha-nitrosamino aldehydes. Five structurally representative nitrosamino-ethanals (R-N(NO)CH2CHO, R = 4-ClC6H4-, CH3-, nBu-, tBu-, HOCH2CH2-) have been synthesized. Each of these compounds demonstrates the unusual property of facile transnitrosation to a secondary amine. Transnitrosation to dimethylamine, pyrrolidine, morpholine and N-methylaniline has been shown. This reaction occurs rapidly at room temperature in organic solvents but is somewhat slower in aqueous buffer due to extensive equilibrium formation of gem diols by hydration of the aldehyde group. In aqueous media the transnitrosation rate increases with increasing pH from 7 to 9 and does not occur at pH 4. Transnitrosation to primary amines results in deamination (benzylamine----benzyl alcohol). The transnitrosation reaction is accompanied by the formation of imines of glyoxal (R - N = CH - CH = N - R) which appear as primary amines and glyoxal in aqueous solution. Other products have also been characterized as well. These chemical and biochemical data, taken together with results in other laboratories, provide strong support for our hypothesis that certain beta-oxidized nitrosamines can be activated to proximate or ultimate carcinogens by biochemical oxidation to produce highly reactive nitrosamines.