Structural Models for Substrates and Inhibitors of Cytochrome P450 Enzymes

Abstract

Although a large number of drugs, chemicals, and endogenous compounds are known as substrates or inhibitors of microsomal cytochrome P450 enzymes, systematic attempts to explore substrate and inhibitor specificity of individual cytochrome P450 species have been occasional. An improved understanding of the specificity of individual cytochrome P450 enzymes, however, is desirable for several reasons. First, animal species differ from each other and from humans with respect to their patterns of cytochrome P450 enzymes involved in detoxication and bioactivation of cytotoxic and genotoxic chemicals. More knowledge of the specificity of these enzymes facilitates the explanation of species differences in metabolism and facilitates the design of chemical toxicity studies. Furthermore, reliable substrate models offer the opportunity to predict whether a drug is likely to be a substrate of a particular cytochrome P450 enzyme and thus whether its plasma concentration and, consequently, its therapeutic effects may be subjected to interindividual variations of the activity of this enzyme. Likewise, more knowledge about structural features of compounds inhibitory for cytochrome P450 enzymes is required, to evaluate whether one drug may be inhibitory for the metabolism of one or more other drugs.