Kinetics of Nitrosamide Formation From Alkylureas, N-Alkylurethans, and Alkylguanidines: Possible Implications for the Etiology of Human Gastric Cancer2

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Abstract
The rate of methylurea nitrosation to give methylnitrosourea was proportional to the concentrations of methylurea, nitrous acid, and hydrogen ion. The reaction rate was very rapid under acidic conditions and was increased by sulfate and phosphate ions. Nitrosation of ethylurea, N-methylurethan, and N-ethylurerhan obeyed similar third-order kinetics, but proceeded at slower rates. Nitrosation of DL-citrulline gave N-δ-nitroso-DL-citrulline, with a rate constant 7% of that for methylurea nitrosation. Nitrosation of methylguanidine gave a 35% yield of methylnitrosourea, but the rate constant at pH 2 was only 0.6% of that for citrulline. A new compound, methylnitrosocyanamide, was produced at shorter times. Nitrosation of N-α-acetyl-L-arginine and L-arginine gave unidentified products with absorption spectra similar to the spectrum of nitrosocitrulline, the rate constants at pH 1 being similar to the rate constant for methylguanidine. The results explain findings by others that feeding nitrite plus alkylureas to rats induces cancer and produces 7-alkylation of guanine in tissue nucleic acids. The results also raise the possibility that intragastric nitrosamide formation could be a significant etiological factor in human gastric cancer, because some nitrosamides induce gastric cancer in animals, and some alkylureas and alkylguanidines e.g., citrulline, arginine, and methylguanidine, occur widely in food. If a man ate a 300-g meal containing 38 mg citrulline and 60 mg sodium nitrite, it was estimated that 2.7 mg citrulline might be nitrosated intragastrically. This could be a significant hazard, if nitrosocitrulline is carcinogenic.

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