title: Modeling cyanide release from nitriles: prediction of cytochrome P450 mediated acute nitrile toxicity.
abstract: 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.
authors.affiliation: Laboratory of Molecular Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: J
authors.initials: J
authors.lastname: Grogan
authors.forename: S C
authors.initials: SC
authors.lastname: DeVito
authors.forename: R S
authors.initials: RS
authors.lastname: Pearlman
authors.forename: K R
authors.initials: KR
authors.lastname: Korzekwa
mesh_terms: D003486:Cyanides / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008956:Models, Chemical; D009570:Nitriles / Q000378:metabolism* / Q000633:toxicity; D013816:Thermodynamics
chemical_list: D003486:Cyanides; D009570:Nitriles; D003577:Cytochrome P-450 Enzyme System