The mutagenic and carcinogenic potency of alpha-CH(pi)-nitrosamines such as N-nitrosodimethylamine (NDMA) is caused by their P450-catalyzed alpha-hydroxylation and subsequent deallcylation, yielding alkyl diazonium ions (R-N N(+)) as potent electrophiles. Alternatively, P450s may also catalyze their denitrosation as metabolic detoxification. DFT calculations at the UB3LYP/LANL2DZ(Fe)/6-31G+**(H,C,N,O, S)//LANL2DZ(Fe)/6-31G(H,C,N,O,S) level of theory show that H-abstraction from the a-C of NDMA as initial metabolic step yields an alpha-nitrosamino radical (center dot CH(2)N(CH(3))NO) as common first intermediate for both the oxidative dealkylation (toxification) and denitrosa-tion (detoxification) pathways. In particular, the calculated kinetic isotope effect for the P450-mediated dealkylation of NDMA is in good agreement with experimental information. The results show further that the initial alpha-hydroxylation of NDMA may proceed in two spin states. Besides a stepwise high-spin (HS, quartet) route with a separate rebound barrier, there is a concerted low-spin (LS, doublet) pathway. Interestingly, the resultant two-state reactivity appears to discriminate between metabolic toxification and detoxification: Evaluation of calculated free energy barriers of the H-abstraction (Delta G(double dagger)) through the Eyring equation suggests that the dealkylation:denitrosation product ratio is governed by the LS:HS ratio of the overall metabolic process. Moreover, inclusion of three further alpha-CH(n)-nitrosamines in the computational analysis demonstrates that the initial H-abstraction barrier is proportional to the C-H bond dissociation enthalpy (BDE) of the substrates, which enables the estimation of spin-averaged reaction barriers through ground-state BDE calculations. The discussion includes also reductive denitrosation pathways that according to current computational evidence appear to be unlikely for aliphatic nitrosamines.