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Concurrent Generation of Methylamine and Nitrite during Denitrosation of N-Nitrosodimethylamine by Rat Liver Microsomes¹

Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [L. K. K., T. A.]; and Department of Biochemistry, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103 [D. W., T. W., C. S. Y.]

With the goal of identifying the organic amine product(s) of enzymatic N-nitrosodimethylamine (NDMA) denitrosation, 4 mM NDMA was incubated with liver microsomes from ethanol-treated rats. The concentrations of dimethylamine and methylamine were determined by derivatization with 2,4-dinitrofluorobenzene followed by gas chromatography-mass spectrometry. There was no net increase in the concentration of dimethylamine during incubation, but the yield of methylamine was equimolar with that of nitrite. Additional incubations of NDMA using acetoneinduced microsomes, 1 mM and 0.1 mM substrate, gave methylamine/nitrite ratios of 0.9 and 0.7, respectively, confirming the quantitative linkage between these two products. Control incubations conducted with pure methylamine or dimethylamine indicated that the secondary amine is not a significant intermediate in the metabolic generation of the primary amine. Experiments with ¹⁵N-labeled NDMA showed that the methylamine nitrogen came from the amino moiety of the nitrosamine. The results suggest that NDMA metabolism is best viewed as a competition between at least two important pathways, demethylation and the presumably deactivating denitrosation route, a formulation which seems to account for the previously reported detection of methylamine as a urinary metabolite of NDMA and for the production of less than theoretical yields of labeled dinitrogen gas during NDMA metabolism.

¹ This work was supported in part by Grant CA-37037 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at National Cancer Institute, Frederick Cancer Research Facility, Building 538, Frederick, MD 21701.

Received 7/22/86. Revised 10/ 8/86. Accepted 10/16/86.