A sensitive method for detecting in vivo formation of N-nitrosomorpholine and its application to rats given low doses of morpholine and sodium nitrite.

Abstract

A method was developed to monitor the in vivo formation of N-nitrosomorpholine. N-Nitroso(2-hydroxyethyl)glycine, a major urinary metabolite of N-nitrosomorpholine, was quantified as its methyl ester-trimethylsilyl ether derivative, using gas chromatography with nitrosamine-specific detection. When the method was applied to rats, the in vivo formation of, or exposure to, as little as 0.6 micrograms of N-nitrosomorpholine could be quantified. The method was also applicable to human urine, with a detection limit of approximately 0.5 micrograms of N-nitroso(2-hydroxyethyl)glycine per 100-ml urine sample. The formation of N-nitrosomorpholine was measured in rats treated by gavage with a wide range of doses of morpholine and NaNO2. Depending on the dose, 0.5 to 12% of the morpholine was nitrosated. N-Nitrosomorpholine formation showed a high degree of variability among rats treated with a given dose of morpholine and NaNO2, but the levels of N-nitrosomorpholine formed were generally in agreement with expectations based on in vitro studies in which dependence on morpholine concentration multiplied by nitrite concentration squared has been established. The formation of N-nitrosomorpholine was also measured in rats administered a diet containing 50 ppm of morpholine and 1000 ppm of NaNO2, a regimen which has been previously shown to induce liver cell tumors in 58% of the animals. The mean daily formation of N-nitrosomorpholine under these conditions was estimated to be 0.88 +/- 0.59 mumol/rat (S.D.), which is high enough to account for the observed tumor incidence. The results of this study provide quantitative support for the assumption that in vivo formation of N-nitrosomorpholine leads to tumor development.

• Authors: S S Hecht, J B Morrison
• Journal: Cancer research (Cancer Res) Vol. 44 Issue 7 Pg. 2873-7 (Jul 1984) ISSN: 0008-5472 [Print] United States
• PMID: 6722816 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carbon Radioisotopes
• Carcinogens
• Morpholines
• Nitrites
• Nitrosamines
• N-nitrosomorpholine
• morpholine
• Sodium Nitrite

Topics

• Animals
• Carbon Radioisotopes
• Carcinogens (metabolism)
• Diet
• Kinetics
• Male
• Morpholines (metabolism)
• Nitrites (metabolism)
• Nitrosamines (analysis, metabolism)
• Rats
• Rats, Inbred F344
• Rats, Inbred Strains
• Sodium Nitrite (metabolism)