Reduction of rat liver carcinogenicity of 4-nitrosomorpholine by alpha-deuterium substitution.

Groups of 30 males Sprague-Dawley rats were given 4-nitrosomorpholine-3,3,5,5-d in their drinking water at concentrations of 0.35 and 0.07 X 10(-3) M for 30 weeks. Two similar groups of rats were simultaneously given unlabeled 4-nitrosomorpholine (NM) at the same malar concentrations; all animals were observed throughout their lives. Those receiving the alpha-deuterium-labeled compound had significantly fewer liver tumors than did the corresponding animals receiving the unlabeled compound. The difference in potency appeared to be at least fivefold, a magnitude consistent with a primary kinetic isotope effect on the carcinogenic action of NM. Thus breakage of a bond linking a hydrogen (deuterium) atom with carbon adjacent to the nitrosamino function may be involved in a rate-limiting step of carcinogenesis by NM.