While the oxidation of xenobiotics by cytochrome P450 usually results in detoxification, some compounds are oxidized to more toxic intermediates. An example is the metabolism of nitriles which can result in cyanide release and acute cyanide toxicity. Although previous attempts to correlate the toxicity of nitriles to their hydrophobicity have been successful within certain groups of nitriles, a diverse series of nitriles correlates poorly with hydrophobicity alone, presumably because other factors are necessary to predict the tendency for P450 mediated cyanide release. Previously, we observed a general rank-order correlation between the calculated stability of a radical and the tendency of a carbon-hydrogen bond to undergo hydrogen atom abstraction by cytochrome P450. Using the AM1 quantum chemical method, it was found that the p-nitrosophenoxy radical had the appropriate thermodynamic symmetry for hydrogen atom abstraction reactions. Using this compound as a model for the cytochrome P450 active oxygen species, a linear correlation was observed between the calculated activation enthalpy of hydrogen abstraction reactions and a combination of heat of reaction and the ionization potential of the radical formed. This relationship was used to develop a predictive model for P450 mediated nitrile toxicity which includes both hydrophobicity and tendencies for P450 oxidations. We are now in the process of expanding this model to include aromatic and olefinic oxidations. In addition, reactants and products for 54 hydroxylation and desaturation reactions were modeled and used to predict the relative tendency for each reaction to occur.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01CP005676-02
Application #
3838459
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Division of Cancer Epidemiology and Genetics
Department
Type
DUNS #
City
State
Country
United States
Zip Code