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 interlinking 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anzenbacher, P. and Anzenbacherova, E., Cytochromes P450 and metabolism of xenobiotics. Cell. Mol. Life Sci., 58, 737–747 (2001).
Coon, M. J., Vaz, A. D., Mcginnity, D. F., and Peng, H. M., Multiple activated oxygen species in P450 catalysis: contributions To specificity in drug metabolism. Drug Metab. Dispos., 26, 1190–1193 (1998).
Cytochrome P450 knowledgebase database, http://cpd.ibmh.msk.su. (2006)
Degtyarenko, K. N. and Archakov, A. I., Molecular evolution of P450 superfamily and P450-containing monooxygenase systems. FEBS Lett., 332, 1–8 (1993).
Gonzalez, F. J., Molecular genetics of the P-450 superfamily. Pharmacol. Ther., 45, 1–38 (1990).
Gonzalez, F. J. and Gelboin, H. V., Human cytochromes P450: evolution and cDNA-directed expression. Environ. Health Perspect., 98, 81–85 (1992).
Graham-Lorence, S. and Peterson, J. A., P450s: structural similarities and functional differences. FASEB J., 10, 206–214 (1996).
Guengerich, F. P. and Parikh, A., Expression of drug-metabolizing enzymes. Curr. Opin. Biotechnol., 8, 623–628 (1997).
Guengerich, F. P., Hosea, N. A., Parikh, A., Bell-parikh, L. C., Johnson, W. W., Gillam, E. M., and Shimada, T., Twenty years of biochemistry of human P450s: purification, expression, mechanism, and relevance to drugs. Drug Metab. Dispos., 26, 1175–1178 (1998).
Halpert, J. R., Domanski, T. L., Adali, O., Biagini, C. P., Cosme, J., Dierks, E. A., Johnson, E. F., Jones, J. P., Ortiz De Montellano, P., Philpot, R. M., Sibbesen, O., Wyatt, W. K., and Zheng, Z., Structure-function of cytochromes P450 and flavin-containing monooxygenases: implications for drug metabolism. Drug Metab. Dispos., 26, 1223–1231 (1998).
Ingelman-Sundberg, M., Human drug metabolising cytochrome P450 enzymes: Properties and polymorphisms. Naunyn Schmiedebergs Arch. Pharmacol., 369, 89–104 (2004).
Lewis, D. F., Eddershaw, P. J., Dickins, M., Tarbit, M. H., and Goldfarb, P. S., Structural determinants of cytochrome P450 substrate specificity, binding affinity and catalytic rate. Chem. Biol. Interact., 115, 175–199 (1998).
Nelson, D. R. and Strobel, H. W., Evolution of cytochrome P-450 proteins. Mol. Biol. Evol., 4, 572–593 (1987).
Nieminen, J., On the centrality in a graph. Scand. J. Psychol., 15, 332–336 (1974).
Pelkonen, O., Turpeinen, M., Hakkola, J., Honkakoski, P., Hukkanen, J., and Raunio, H., Inhibition and induction of human cytochrome P450 enzymes: current status. Arch. Toxicol., 82, 667–715 (2008).
R project, http://www.r-project.org/.
Sabidussi, G., The centrality of a graph. Psychometrika, 31, 581–603 (1966).
Shannon, P., Markiel, A., Ozier, O., Baliga, N. S., Wang, J. T., Ramage, D., Amin, N., Schwikowski, B., and Ideker, T., Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 13, 2498–2504 (2003).
Sneath, P. H., The application of computers to taxonomy. J. Gen. Microbiol., 17, 201–226 (1957).
Spatzenegger, M. and Jaeger, W., Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab. Rev., 27, 397–417 (1995).
Szklarz, G. D. and Halpert, J. R., Molecular basis of P450 inhibition and activation: implications for drug development and drug therapy. Drug Metab. Dispos., 26, 1179–1184 (1998).
Tian, W. and Skolnick, J., How well is enzyme function conserved as a function of pairwise sequence identity? J. Mol. Biol., 333, 863–882 (2003).
Wong, L. L., Cytochrome P450 monooxygenases. Curr. Opin. Chem. Biol., 2, 263–268 (1998).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, S., Kim, D. Cytochrome P450 networks in chemical space. Arch. Pharm. Res. 33, 1361–1374 (2010). https://doi.org/10.1007/s12272-010-0910-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12272-010-0910-1