Modeling cyanide release from nitriles: prediction of cytochrome P450 mediated acute nitrile toxicity.
A mechanism-based model for prediction of acute nitrile toxicity was developed using octanol-water partition coefficients (log P) and estimated rates of alpha-hydrogen atom abstraction as variables. Relative rates of hydrogen atom abstraction were derived from differences in heats of formation for ground-state and radical geometries and radical ionization potentials. Calculated energies of activation for all potential sites of oxidation for a given nitrile were used to estimate partitioning of metabolites among multiple oxidative pathways. logP and the resulting corrected rate constants for alpha-carbon oxidation were effective variables in an acute toxicity model of structurally diverse nitriles. The pharmacokinetics of substrate disposition is discussed in the context of multiple metabolic pathways. Structure-toxicity relationships are also discussed.
Grogan
J
J
Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892.
DeVito
S C
SC
Pearlman
R S
RS
Korzekwa
K R
KR
D003486:Cyanides / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008956:Models, Chemical; D009570:Nitriles / Q000378:metabolism* / Q000633:toxicity; D013816:Thermodynamics
D003486:Cyanides; D009570:Nitriles; D003577:Cytochrome P-450 Enzyme System