Publication Details |
| Category | Text Publication |
| Reference Category | Journals |
| DOI | 10.1021/jp206570n |
| Title (Primary) | Computational evidence for α-nitrosamino radical as initial metabolite for both the P450 dealkylation and denitrosation of carcinogenic nitrosamines |
| Author | Ji, L.; Schüürmann, G. |
| Source Titel | Journal of Physical Chemistry B |
| Year | 2012 |
| Department | OEC |
| Volume | 116 |
| Issue | 2 |
| Page From | 903 |
| Page To | 912 |
| Language | englisch |
| Abstract | The mutagenic and carcinogenic potency of α-CHn-nitrosamines such as N-nitrosodimethylamine (NDMA) is caused by their P450-catalyzed α-hydroxylation and subsequent dealkylation, 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 α-C of NDMA as initial metabolic step yields an α-nitrosamino radical (•CH2N(CH3)NO) as common first intermediate for both the oxidative dealkylation (toxification) and denitrosation (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 α-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 (ΔG‡) 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 α-CHn-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. |
| Persistent UFZ Identifier | https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=12117 |
| Ji, L., Schüürmann, G. (2012): Computational evidence for α-nitrosamino radical as initial metabolite for both the P450 dealkylation and denitrosation of carcinogenic nitrosamines J. Phys. Chem. B 116 (2), 903 - 912 10.1021/jp206570n |
|