A STUDY OF CHEMICAL CARCINOGENESIS .35. METABOLIC ALPHA-HYDROXYLATION OF N-NITROSOMORPHOLINE AND 3,3,5,5-TETRADEUTERO-N-NITROSOMORPHOLINE IN THE F344 RAT

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (12) , 5039-5043
Abstract
The metabolism in the male F344 rat of N-nitrosomorpholine and 3,3,5,5-tetradeutero-N-nitrosomorpholine was studied; the latter is less carcinogenic and less mutagenic than is N-nitrosomorpholine. .alpha.-Hydroxylation (3- or 5-hydroxylation) of N-nitrosomorpholine by liver microsomes and a reduced NADP-generating system produced (2-hydroxyethoxy)acetaldehyde, which was identified as its 2,4-dinitrophenylhydrazone derivative. When N-nitrosomorpholine was administered to rats i.p., (2-hydroxyethoxy)acetaldehyde was not detected in the urine, but (2-hydroxyethoxy)acetic acid (16% of the dose) was identified. N-nitroso(2-hydroxyethyl)glycine (33% of the dose) from .beta.-hydroxylation (2- or 6-hydroxylation), N-nitrosodiethanolamine (12%) and unchanged N-nitrosomorpholine (1.5%) were identified 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%). Deuterium substitution in the .alpha.-positions of N-nitrosomorpholine caused a decrease in the extent of .alpha.-hydroxylation and .alpha.-hydroxylation is apparently the mechanism of activation of N-nitrosomorpholine.