Alladi Ramakrishnan Hall

Systems biology and network biology applications in Toxicology: Examples from Cytochrome P450 enzyme system and Obesogens

B. S. Karthikeyan

Bharathidasan University, Tiruchirappalli

The post genomic era aims at cataloguing the relationships among cellular components that would help to understand emergent properties at the system level. Cytochrome P450 (CYP) enzymes that degrade xenobiotics play a critical role in the metabolism and biotransformation of drugs and xenobiotics in humans as well as experimental animal models such as mouse and rat. These proteins function as a network collectively as well as independently. Though there are several reports on the organization, regulation and functionality of various CYP enzymes at the molecular level, the understanding of organization and functionality of these proteins at the holistic level remain unclear. The objective of this study has been to understand the organization and functionality of xenobiotic degrading CYP enzymes of human, mouse and rat using network theory approaches and to study species differences that exist among them at the holistic level. For this analysis, a Protein-protein interaction (PPI) network for CYP enzymes of human, mouse and rat was constructed using the STRING database. Topology, centrality, modularity and robustness analyses were performed for our predicted CYP PPI networks that were then validated by comparison with randomly generated network models. Network centrality analyses of CYP PPI networks reveal the central/hub proteins in the network. Modular analysis of the CYP PPI networks of human, mouse and rat resulted in functional clusters. These clusters were subjected to ontology and pathway enrichment analysis. The analyses show that the cluster of the human CYP PPI network is enriched with pathways principally related to xenobiotic/drug metabolism. Endo-xenobiotic crosstalk dominated in mouse and rat CYP PPI networks, and they were highly enriched with endogenous metabolic and signaling pathways. Thus, cross-species comparisons and analyses of human, mouse and rat CYP PPI networks gave insights about species differences that existed at the holistic level.
In another study, we employed systems chemical biology approach to investigate the system-level effect of 54 obesogenic compounds on human protein interaction network by constructing obesogen targeting protein interaction (OTPI) network using STITCH database. Obesogens are exogenous chemicals that have potential to alter lipid homeostasis and metabolic set points which enhance storage of fat. Although the effect of few obesogens on human molecular targets was extensively reported, the influence of obesogens on protein interaction networks at system-level remains unclear. Topology and centrality analysis of OTPI network reveals the central/hub proteins of the network. Modular analysis of the OTPI network resulted in functionally important clusters in the network. Functional enrichment analysis of OTPI network reveals functionality of interacting proteins that are enriched in key functions and processes such as adipocyte differentiation, glucocorticoid receptor signaling, energy homeostasis and signal transduction pathways.
Thus systems biology and network biology applications in toxicology helps to understand species differences among Cytochrome P450 enzyme system of human, mouse and rat and as well as to dissect complexity of obesogens.