An azole compound is considered to be a good probe for analyzing the binding affinity with various cytochrome P450 (CYP) proteins because of its coordination ability regarding the heme iron in the proteins. Eighteen azole compounds including commercial fungicides were examined for their binding to rat liver microsomal CYP2B and CYP3A using a type II spectral change. The binding affinities determined were analyzed in relation to the molecular properties of the azole compounds. Good correlation with the bilinear model was observed between the binding affinities and the partition coefficient (log P). The model suggested that the optimum log P values of the azole compounds were nearly the same for these two CYPs. The sequence homology of amino acid residues around the substrate recognition site is significantly high between CYP2B and CYP3A. It was reported that sizes of the binding pocket in CYP2B and CYP3A are not much different. These explain why the optimum log P values in the correlation equations for CYP2B and CYP3A was nearly the same.

Azole compounds are widely used as antifungal agents. They interact with cytochrome P450 14DM (CYP51) via coordination of the nucleophilic nitrogen of their heterocyclic ring to the heme iron in CYP51. In our previous study, we showed that the binding affinity of eighteen azole compounds for rat CYP2B and CYP3A was nicely expressed by the bilinear model of log P. In this study, the same azole compounds were examined as to their inhibitory effect on the substrates for human CYP2B6 and CYP3A4. The inhibitory activity determined was analyzed as to the molecular properties of the azole compounds. A nice correlation was found with the bilinear model of log P. These results suggested that the molecular hydrophobicity of the azole compounds plays a major role in the inhibition as well as in the binding. For the binding, HOMO was significant as an additional descriptor in the correlation equations, whereas the existence of a hydroxyl group was significant for the inhibition.