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Evolution of 5N2-labeled molecular nitrogen was used to gauge the extent of a-hydroxylation during rat liver homogenate metabolism of doubly '5N-labeled N-nitrosodimethylamine (DMN) and N-nitrosomethylaniline (NMA). These measurements were correlated with the extent of total metabolism as measured by the Except for certain special cases, N-nitrosamines must be activated metabolically before their carcinogenic or mutagenic potential can be expressed. In the most widely held hypothesis, the metabolic activation involves the hydroxylation of the acarbon (1) (Fig. 1). The initially formed a-hydroxymethyl (or alkyl, in the general case) nitrosamine is unstable and undergoes a fragmentation reaction to the diazonium ion and formaldehyde. The former reacts with any adventitious nucleophiles to give alkylation products and 1 equivalent ofmolecular nitrogen. The formation ofmolecular nitrogen in principle should provide a convenient probe of the extent of a-hydroxylation.The determination of nitrogen as a measure of a-hydroxylation has been investigated previously. The published reports, however, are dramatically contradictory. Cottrell et aL (2) reported that less than 5% of the metabolism of N-nitrosodimethylamine (DMN) by postmitochondrial rat liver homogenates (S9 fraction) led to the formation of molecular nitrogen. These workers used doubly '5N-labeled DMN. On the other hand, Milstein and Guttenplan (3) used unlabeled DMN and microsomes and found that essentially all ofthe nitrosamine was metabolized by the a-hydroxylation pathway.The extent of a-hydroxylation in the metabolism of two nitrosamines, DMN and N-nitroso-N-methylaniline (NMA), by rat S9 fraction is reported here.

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