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Metabolism of N-Nitrosamines by Cultured Human and Rat Esophagus

Carcinogen Macromolecular Interaction Section, Laboratory of Human Carcinogenesis, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda, Maryland 20205 [H. A.], and Department of Pathology, Medical College of Ohio, Toledo, Ohio 43614 [G. D. S.]

The metabolism of several N-nitrosamines (N-nitrosodimethylamine, N-nitrosoethylmethylamine, N-nitrosodiethylamine, N-nitrosobenzylmethylamine, and N-nitrosopyrrolidine) in cultured human and rat esophagus has been investigated by measuring (a) CO₂, (b) metabolites with and oxo group, and (c) metabolites bound to DNA. Both acyclic and cyclic N-nitrosamines were metabolized by rat esophagus. The highest level of metabolite binding was seen with N-nitrosobenzylmethylamine, an organotrophic carcinogen for the rat esophagus. The binding level was about 100-fold higher than in human esophagus. This compound methylated rat esophageal DNA at positions 7 and O⁶ of guanine. The level of benzylation in rat was one-tenth the level of methylation. Formation of benzaldehyde exceeded that of formaldehyde plus CO₂ by a factor of six, indicating that the methylene group was preferentially oxidized. N-Nitrosoethylmethylamine, another unsymmetrical N-nitrosamine, was preferentially oxidized by rat esophagus in the ethyl group, as shown by higher formation of CO₂ and acetaldehyde from the compound labeled in the ethyl group. The highest binding level to DNA from this compound was observed with the methyl group. No binding was detected to human esophagus. N-Nitrosopyrrolidine was oxidized by both rat and human esophagus in the position, as measured by the formation of 2,4-dinitrophenylhydrazone derivative of 4-hydroxybutanal. Binding of metabolites of N-nitrosopyrrolidine to DNA was detected only in rat esophagus. As measured by the formation of both CO₂ and formaldehyde, N-nitrosodimethylamine was metabolized by both human and rat esophagus. While most of the radioactivity associated with DNA was found to be incorporated into guanine and adenine, methylation of the guanine positions 7 and O⁶ was detected by chromatography of the hydrolyzed rat DNA. The results indicate significant quantitative and perhaps qualitative differences between cultured rat and human esophagus in their ability to activate N-nitrosamines, although unknown physiological differences after culture may contribute to this difference.

¹ To whom requests for reprints should be addressed, at National Cancer Institute, NIH, Building 37, Room 2C13, Bethesda, Md. 20205.

Received 2/19/82. Accepted 12/15/81.

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