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Nitrosamine carcinogen activation pathway determined by quantum chemical methods.
M Poulsen1, D Spangler, G H Loew
1Life Sciences Division, SRI International, Menlo Park, California.
Molecular Toxicology
|January 1, 1987
Summary
Computational chemistry reveals how dialkynitrosamines form carcinogens. A direct, concerted pathway is favored over a two-step mechanism for generating active carcinogens like diazohydroxides.
Area of Science:
- Computational chemistry
- Biochemistry
- Toxicology
Background:
- Dialkynitrosamines are precursors to active carcinogens.
- Cytochrome P-450 enzymes initiate carcinogen formation via alpha-hydroxylation.
- Subsequent nonenzymatic steps generate ultimate carcinogens, such as diazohydroxides.
Purpose of the Study:
- To investigate the reaction mechanisms for transforming dialkynitrosamines into active carcinogens.
- To compare the kinetic favorability of different pathways for diazohydroxide formation.
- To elucidate the role of computational methods in understanding carcinogen activation.
Main Methods:
- Utilized semiempirical molecular orbital method MNDO (modified neglect of diatomic differential overlap).
- Employed ab initio methods with STO-3G and 3-21G basis sets.
- Performed complete geometry optimizations for all reaction species, including transition states.
Main Results:
- A concerted, six-membered ring transition-state pathway is kinetically favored over a two-step mechanism in the gas phase.
- The direct pathway efficiently forms diazohydroxides and formaldehyde from hydroxymethylnitrosamine.
- Comparison with dimethylnitrosamine transformation using MNDO showed similar trends.
Conclusions:
- The direct, concerted pathway is the preferred route for generating ultimate carcinogens from dialkynitrosamines.
- This mechanism is likely operative within the hydrophobic binding site of cytochrome P-450.
- Computational modeling provides valuable insights into carcinogen activation pathways.