Systems biology tools for toxicology

Abstract

An important goal of toxicology is to understand and predict the adverse effects of drugs and other xenobiotics. For pharmaceuticals, such effects often emerge unexpectedly in man even when absent from trials in vitro and in animals. Although drugs and xenobiotics act on molecules, it is their perturbation of intracellular networks that matters. The tremendous complexity of these networks makes it difficult to understand the effects of xenobiotics on their ability to function. Because systems biology integrates data concerning molecules and their interactions into an understanding of network behaviour, it should be able to assist toxicology in this respect. This review identifies how in silico systems biology tools, such as kinetic modelling, and metabolic control, robustness and flux analyse, may indeed help understanding network-mediated toxicity. It also shows how these approaches function by implementing them vis-à-vis the glutathione network, which is important for the detoxification of reactive drug metabolites. The tools enable the appreciation of the steady state concept for the detoxification network and make it possible to simulate and then understand effects of perturbations of the macromolecules in the pathway that are counterintuitive. We review how a glutathione model has been used to explain the impact of perturbation of the pathway at various molecular sites, as would be the effect of single-nucleotide polymorphisms. We focus on how the mutations impact the levels of glutathione and of two candidate biomarkers of hepatic glutathione status. We conclude this review by sketching how the various systems biology tools may help in the various phases of drug development in the pharmaceutical industry.

Strategies for Minimisation of the Cholestatic Liver Injury Liability Posed by Drug-Induced Bile Salt Export Pump (BSEP) Inhibition

“…Kenna et al most notably via reactive metabolite formation (e.g., [114,115]), and may offer an opportunity to address some of these questions and improve the prediction of DILI potential caused by BSEP inhibition. The ITC has highlighted BSEP as one of the emerging transporters that needs to be considered when evaluating drug safety.…”

The Application of Omics Technologies to the Study of Mammalian Toxicology

“…Other research groups have framed systems toxicology as a means of providing a unifying hypothesis for cardiotoxic drugs [103] or groups of related diseases, such as Fenton chemistry-based neurodegeneration from cellular iron dysregulation [104]. At present, singular studies are somewhat limited that make global measurements of biomolecules representing significant portions of biology that take into account changes over time to formulate mathematical models from which predictions can be made [105][106][107][108].…”

A foresight study on emerging technologies: State of the art of Omics technologies and potential applications in food and feed safety

“…Systems biology is being considered as a tool to improve this understanding. Systems biology is the scientific discipline that encompasses and describes relationships between different types of omics findings and physiology (Geenen et al, 2012). Preferably, knowledge is used that is based on confirmed findings.…”