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Metabolic -Hydroxylation of N-Nitrosomorpholine and 3,3,5,5-Tetradeutero-N-nitrosomorpholine in the F344 Rat^1,2,

Division of Chemical Carcinogenesis, American Health Foundation, Naylor Dana Institute for Disease Prevention, Valhalla, New York 10595

We studied the metabolism in the male F344 rat of N-nitrosomorpholine and of 3,3,5,5-tetradeutero-N-nitrosomorpholine; the latter is less carcinogenic and less mutagenic than is N-nitrosomorpholine. -Hydroxylation (3- or 5-hydroxylation) of N-nitrosomorpholine by liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system produced (2-hydroxyethoxy)acetaldehyde, which was identified as its 2,4-dinitrophenylhydrazone derivative. When we administered N-nitrosomorpholine to rats i.p., we did not detect (2-hydroxyethoxy)acetaldehyde in the urine, but we did identify (2-hydroxyethoxy)acetic acid (16% of the dose). We also identified N-nitroso(2-hydroxyethyl)glycine (33% of the dose) from ß-hydroxylation (2- or 6-hydroxylation), N-nitrosodiethanolamine (12%), and unchanged N-nitrosomorpholine (1.5%) in the urine. The deuterated analogs of the above metabolites were isolated from the urine of rats treated with 3,3,5,5-tetradeutero-N-nitrosomorpholine in yields as follows: (2-hydroxyethoxy)acetic acid (3.4%); N-nitroso(2-hydroxyethyl)glycine (37%); N-nitrosodiethanolamine (12%); N-nitrosomorpholine (0.4%). These data demonstrate that deuterium substitution in the -positions of N-nitrosomorpholine caused a decrease in the extent of -hydroxylation and indicate that -hydroxylation is the mechanism of activation of N-nitrosomorpholine.

¹ This work was supported by National Cancer Institute Grant CA23901. This is Paper 35 of the series, "A Study of Chemical Carcinogenesis."

² This publication is dedicated to the founder of the American Health Foundation, Dr. Ernst L. Wynder, on the occasion of the 10th anniversary of the Naylor Dana Institute for Disease Prevention.

³ To whom requests for reprints should be addressed.

Received 5/29/81. Accepted 8/ 3/81.