Cytochrome P450 Networks in Chemical Space

Abstract

A global analysis of the chemical space of cytochrome P450 enzymes in humans has not been achieved despite its great importance for drug metabolism and drug-drug interactions. We analyzed the global characteristics of cytochrome P450s by building several networks at the family, subfamily, and gene levels from information on P450 substrates, inducers, and inhibitors. These networks provide insight into the relationship of cytochrome P450 isoforms on the metabolism of drugs, changes in drug activity, and the promiscuous properties of each cytochrome P450 enzyme. From the networks, we analyzed the centrality of nodes and measured the strength of correlations between two nodes by drawing promiscuity maps. In addition, heat maps were generated to cluster cytochrome P450s by their similarity within three chemical spaces (substrates, inducers, and inhibitors). We observed the intra-linking and inter-linking connections between three chemical spaces, the relative correlations of a given cytochrome P450 isoform with other isoforms, and the similarity of the metabolizing ability and changing pattern by chemicals. These results provide a global view of the relationship and similarity of cytochrome P450s on various chemical spaces at various levels. The measures of the strength of connection between two cytochrome P450s and the heat-map information could be used to predict drug-drug interactions, perform phylogenetic analyses, and further understand cooperative properties of these enzymes.