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Metabolic Denitrosation of N-Nitrosodimethylamine in Vivo in the Rat

Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [A. J. S., R. W. N., P. R. S., Y-H. H., L. K. K.] Department of Chemical Biology and Pharmacognosy, Rutgers University, Piscataway, New Jersey 09955 [C. S. Y.]; Department of Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [B. A. M.]; and Department of Drug Metabolism, Smith, Kline & French Laboratories, Philadelphia, Pennsylvania 19101 [C. T. G.]

Enzymatic denitrosation is a potentially inactivating metabolic route that has been shown to convert carcinogenic N-nitrosodimethylamine (NDMA) to methylamine (MA) in vitro. To investigate its quantitative course in vivo, groups of 8-week-old male Fischer rats have been given small (8–15 µmol/kg) p.o. or i.v. bolus doses of ¹⁴C-labeled NDMA and the subsequent formation of radioactive MA has been monitored by high performance liquid chromatographic analysis of serially collected blood samples from each individual. Adjusting the [¹⁴C]MA fluxes observed for the previously measured rates at which MA is itself eliminated from the system after intragastric administration, denitrosation was calculated to represent a rather uniform 21.3 ± 1.3% (SE) of total NDMA elimination in the four animals studied. By contrast, repetition of the experiment with fully deuterated NDMA (NDMA-d₆) revealed a significantly wider variance in the results (39.8 ± 8.9%). An alternative calculation using values for elimination of i.v. doses of MA and its trideuteromethyl analogue gave an even larger difference for MA formation between NDMA and NDMA-d₆, the estimated extents of in vivo denitrosation in this case being 14.5 ± 0.9% and 48.3 ± 10.8%, respectively. The results indicate that denitrosation is a major metabolic pathway for NDMA elimination and suggest that deuteration of the carcinogen induces a shift in its metabolism toward increasing denitrosation at the expense of the competing activation pathway. Consequently, denitrosation may be the previously undefined in vivo metabolic route, the existence of which was suggested by the findings that deuteration of NDMA lowered its hepatocarcinogenicity and liver DNA alkylating ability in rats.

¹ To whom requests for reprints should be addressed, c/o NCI-FCRF, Bldg. 538, Frederick, MD 21701.

Received 7/ 5/89. Revised 11/ 6/89. Accepted 11/14/89.

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