The role of hydrophobicity and electronic factors in regulating alcohol inhibition of cytochrome P-450-mediated aniline hydroxylation

The role of hydrophobicity and electronic factors in regulating alcohol inhibition of cytochrome P-450-mediated aniline p-hydroxylation has been investigated by the formulation of quantitative structure-activity relationships. The activity of linear primary alcohols and unhindered linear secondary alcohols shows a linear dependence on log P, where P is the octanol-water partition coefficient. Hindered primary and secondary alcohols are less active than this relationship predicts. An equation describing the activity of both hindered and unhindered primary and secondary alcohols shows that alcohol inhibition of aniline hydroxylation is regulated by hydrophobicity and steric effects. No role for electronic factors can be discerned. Similarities are found between alcohol inhibition and the binding of alkyl amines to cytochrome P-450, suggesting that alcohols may bind to the amine binding site.